1,3-Diamino-2-hydroxypropane pro-drug derivatives

ABSTRACT

The present invention relates to compounds of formula (AA) (I) and (X): 
                         
useful in treating Alzheimer&#39;s disease and other similar diseases. These compounds include inhibitors of the beta-secretase enzyme that are useful in the treatment of Alzheimer&#39;s disease and other diseases characterized by deposition of A beta peptide in a mammal. The compounds of the invention are useful in pharmaceutical compositions and methods of treatment to reduce A beta peptide formation.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Provisional Application Ser. No. 60/408,783, filed Sep. 6, 2002, which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to 1,3-diamino-2-hydroxypropane prodrug derivatives and to such compounds that are useful in the treatment of Alzheimer's disease and related diseases. More specifically, it relates to such compounds that are capable of yielding or generating, either in vitro or in vivo, compounds that inhibit beta-secretase, an enzyme that cleaves amyloid precursor protein to produce amyloid beta peptide (A beta), a major component of the amyloid plaques found in the brains of Alzheimer's sufferers.

2. Background of the Invention

Alzheimer's disease (AD) is a progressive degenerative disease of the brain primarily associated with aging. Clinical presentation of AD is characterized by loss of memory, cognition, reasoning, judgment, and orientation. As the disease progresses, motor, sensory, and linguistic abilities are also affected until there is global impairment of multiple cognitive functions. These cognitive losses occur gradually, but typically lead to severe impairment and eventual death in the range of four to twelve years.

Alzheimer's disease is characterized by two major pathologic observations in the brain: neurofibrillary tangles and beta amyloid (or neuritic) plaques, comprised predominantly of an aggregate of a peptide fragment know as A beta. Individuals with AD exhibit characteristic beta-amyloid deposits in the brain (beta amyloid plaques) and in cerebral blood vessels (beta amyloid angiopathy) as well as neurofibrillary tangles. Neurofibrillary tangles occur not only in Alzheimer's disease but also in other dementia-inducing disorders. On autopsy, large numbers of these lesions are generally found in areas of the human brain important for memory and cognition.

Smaller numbers of these lesions in a more restricted anatomical distribution are found in the brains of most aged humans who do not have clinical AD. Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), and other neurodegenerative disorders. Beta-amyloid is a defining feature of AD, now believed to be a causative precursor or factor in the development of disease. Deposition of A beta in areas of the brain responsible for cognitive activities is a major factor in the development of AD. Beta-amyloid plaques are predominantly composed of amyloid beta peptide (A beta, also sometimes designated betaA4). A beta peptide is derived by proteolysis of the amyloid precursor protein (APP) and is comprised of 39-42 amino acids. Several proteases called secretases are involved in the processing of APP.

Cleavage of APP at the N-terminus of the A beta peptide by beta-secretase and at the C-terminus by one or more gamma-secretases constitutes the beta-amyloidogenic pathway, i.e. the pathway by which A beta is formed. Cleavage of APP by alpha-secretase produces alpha-sAPP, a secreted form of APP that does not result in beta-amyloid plaque formation. This alternate pathway precludes the formation of A beta peptide. A description of the proteolytic processing fragments of APP is found, for example, in U.S. Pat. Nos. 5,441,870; 5,721,130; and 5,942,400.

An aspartyl protease has been identified as the enzyme responsible for processing of APP at the beta-secretase cleavage site. The beta-secretase enzyme has been disclosed using varied nomenclature, including BACE, Asp, and Memapsin. See, for example, Sinha et al., 1999, Nature 402:537-554 (p501) and published PCT application WO00/17369.

Several lines of evidence indicate that progressive cerebral deposition of beta-amyloid peptide (A beta) plays a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, for example, Selkoe, 1991, Neuron 6:487. Release of A beta from neuronal cells grown in culture and the presence of A beta in cerebrospinal fluid (CSF) of both normal individuals and AD patients has been demonstrated. See, for example, Seubert et al., 1992, Nature 359:325-327.

It has been proposed that A beta peptide accumulates as a result of APP processing by beta-secretase, thus inhibition of this enzyme's activity is desirable for the treatment of AD. In vivo processing of APP at the beta-secretase cleavage site is thought to be a rate-limiting step in A beta production, and is thus a therapeutic target for the treatment of AD. See for example, Sabbagh, M., et al., 1997, Alz. Dis. Rev. 3, 1-19.

BACE1 knockout mice fail to produce A beta, and present a normal phenotype. When crossed with transgenic mice that over express APP, the progeny show reduced amounts of A beta in brain extracts as compared with control animals (Luo et al., 2001 Nature Neuroscience 4:231-232). This evidence further supports the proposal that inhibition of beta-secretase activity and reduction of A beta in the brain provides a therapeutic method for the treatment of AD and other beta amyloid disorders.

At present there are no effective treatments for halting, preventing, or reversing the progression of Alzheimer's disease. Therefore, there is an urgent need for pharmaceutical agents capable of slowing the progression of Alzheimer's disease and/or preventing it in the first place.

Compounds that are effective inhibitors of beta-secretase, that inhibit beta-secretase-mediated cleavage of APP, that are effective inhibitors of A beta production, and/or are effective to reduce amyloid beta deposits or plaques, are needed for the treatment and prevention of disease characterized by amyloid beta deposits or plaques, such as AD.

SUMMARY OF THE INVENTION

The invention encompasses the compounds of formula (AA), (I) and (X) shown below, pharmaceutical compositions containing the compounds and methods employing such compounds or compositions in the treatment of Alzheimer's disease and more specifically compounds that are capable of inhibiting beta-secretase, an enzyme that cleaves amyloid precursor protein to produce A-beta peptide, a major component of the amyloid plaques found in the brains of Alzheimer's sufferers.

In one aspect, the invention provides compounds of the formula AA:

-   and pharmaceutically acceptable salts thereof, wherein one of R_(N)     and R_(N)′ is hydrogen and -   the other is —C(═O)—(CRR′)₀₋₆R₁₀₀, —C(═O)—(CRR′)₁₋₆—O—R′₁₀₀,     —C(═O)—(CRR′)₁₋₆—S—R′₁₀₀, —C(═O)—(CRR′)₁₋₆—C(═O)—R₁₀₀,     —C(═O)—(CRR′)₁₋₆—SO₂—R₁₀₀, —C(═O)—(CRR′)₁₋₆—NR₁₀₀—R′₁₀₀, or

-   -   wherein

-   R₄ is selected from the group consisting of H; NH₂;     —NH—(CH₂)_(n6)—R₄₋₁; —NHR₈; —NR₅₀C(O)R₅; C₁-C₄ alkyl-NHC(O)R₅;     —(CH₂)₀₋₄R₈; —O—C₁-C₄ alkanoyl; OH; C₆-C₁₀ aryloxy optionally     substituted with 1, 2, or 3 groups that are independently halogen,     C₁-C₄ alkyl, —CO₂H, —C(O)—C₁-C₄ alkoxy, or C₁-C₄ alkoxy; C₁-C₆     alkoxy; aryl C₁-C₄ alkoxy; —NR₅₀CO₂R₅₁; —C₁—C₄ alkyl-NR₅₀CO₂R₅₁;     —C≡N; —CF₃; —CF₂—CF₃; —C≡CH; —CH₂—CH═CH₂; —(CH₂)₁₋₄—R₄₋₁;     —(CH₂)₁₋₄—NH—R₄₋₁; —O—(CH₂)_(n6)—R₄₋₁; —S—(CH₂)_(n6)—R₄₋₁;     —(CH₂)₀₋₄—NHC(O)—(CH₂)₀₋₆—R₅₂; —(CH₂)₀₋₄—R₅₃—(CH₂)₀₋₄—R₅₄;     -   wherein         -   n₆ is 0, 1, 2, or 3;         -   n₇ is 0, 1, 2, or 3;     -   R₄₋₁ is selected from the group consisting of —SO₂—(C₁-C₈         alkyl), —SO—(C₁-C₈ alkyl), —S—(C₁-C₈ alkyl), —S—CO—(C₁-C₆         alkyl), —SO₂—NR₄₋₂R₄₋₃; —CO—C₁-C₂ alkyl; —CO—NR₄₋₃R₄₋₄;     -   R₄₋₂ and R₄₋₃ are independently H, C₁-C₃ alkyl, or C₃-C₆         cycloalkyl;     -   R₄₋₄ is alkyl, arylalkyl, alkanoyl, or arylalkanoyl;     -   R₄₋₆ is —H or C₁-C₆ alkyl;     -   R₅ is selected from the group consisting of C₃-C₇ cycloalkyl;         C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that         are independently halogen, —NR₆R₇, C₁-C₄ alkoxy, C₅-C₆         heterocycloalkyl, C₅-C₆ heteroaryl, C₆-C₁₀ aryl, C₃-C₇         cycloalkyl C₁-C₄ alkyl, —S—C₁-C₄ alkyl, —SO₂—C₁-C₄ alkyl, —CO₂H,         —CONR₆R₇, —CO₂—C₁-C₄ alkyl, C₆-C₁₀ aryloxy; heteroaryl         optionally substituted with 1, 2, or 3 groups that are         independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₁-C₄         haloalkyl, or OH; heterocycloalkyl optionally substituted with         1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄         alkoxy, halogen, or C₂-C₄ alkanoyl; aryl optionally substituted         with 1, 2, 3, or 4 groups that are independently halogen, OH,         C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₁-C₄ haloalkyl; and —NR₆R₇;         wherein R₆ and R₇ are independently selected from the group         consisting of H, C₁-C₆ alkyl, C₂-C₆ alkanoyl, phenyl, —SO₂—C₁-C₄         alkyl, phenyl C₁-C₄ alkyl;     -   R₈ is selected from the group consisting of —SO₂-heteroaryl,         —SO₂-aryl, —SO₂-heterocycloalkyl, —SO₂—C₁-C₁₀ alkyl, —C(O)NHR₉,         heterocycloalkyl, —S—C₁-C₆ alkyl, —S—C₂-C₄ alkanoyl, wherein         -   R₉ is aryl C₁-C₄ alkyl, C₁-C₆ alkyl, or H; R₅₀ is H or C₁-C₆             alkyl;     -   R₅₁ is selected from the group consisting of aryl C₁-C₄ alkyl;         C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that         are independently halogen, cyano, heteroaryl, —NR₆R₇,         —C(O)NR₆R₇, C₃-C₇ cycloalkyl, or —C₁-C₄ alkoxy; heterocycloalkyl         optionally substituted with 1 or 2 groups that are independently         C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₂-C₄ alkanoyl, aryl C₁-C₄         alkyl, and —SO₂ C₁-C₄ alkyl; alkenyl; alkynyl; heteroaryl         optionally substituted with 1, 2, or 3 groups that are         independently OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, NH₂,         NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl)(C₁-C₆ alkyl); heteroarylalkyl         optionally substituted with 1, 2, or 3 groups that are         independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, NH₂, NH(C₁-C₆         alkyl) or N(C₁-C₆ alkyl)(C₁-C₆ alkyl); aryl; heterocycloalkyl;         C₃-C₈ cycloalkyl; and cycloalkylalkyl; wherein the aryl;         heterocycloalkyl, C₃-C₈ cycloalkyl, and cycloalkylalkyl groups         are optionally substituted with 1, 2, 3, 4 or 5 groups that are         independently halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆         alkanoyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, hydroxy, C₁-C₆         hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ thioalkoxy, C₁-C₆         thioalkoxy C₁-C₆ alkyl, or C₁-C₆ alkoxy C₁-C₆ alkoxy;     -   R₅₂ is heterocycloalkyl, heteroaryl, aryl, cycloalkyl,         —S(O)₀₋₂—C₁-C₆ alkyl, CO₂H, —C(O)NH₂, —C(O)NH(alkyl),         —C(O)N(alkyl) (alkyl), —CO₂-alkyl, —NHS(O)₀₋₂—C₁-C₆ alkyl,         —N(alkyl)S(O)₀₋₂—C₁-C₆ alkyl, —S(O)₀₋₂-heteroaryl,         —S(O)₀₋₂-aryl, —NH(arylalkyl), —N(alkyl) (arylalkyl),         thioalkoxy, or alkoxy, each of which is optionally substituted         with 1, 2, 3, 4, or 5 groups that are independently alkyl,         alkoxy, thioalkoxy, halogen, haloalkyl, haloalkoxy, alkanoyl,         NO₂, CN, alkoxycarbonyl, or aminocarbonyl;     -   R₅₃ is absent, —O—, —C(O)—, —NH—, —N(alkyl)-, —NH—S(O)₀₋₂—,         —N(alkyl)-S(O)₀₋₂—, —S(O)₀₋₂—NH—, —S(O)₀₋₂—N(alkyl)-, —NH—C(S)—,         or —N(alkyl)-C(S)—;     -   R₅₄ is heteroaryl, aryl, arylalkyl, heterocycloalkyl, CO₂H,         —CO₂-alkyl, —C(O)NH(alkyl), —C(O)N(alkyl) (alkyl), —C(O)NH₂,         C₁-C₈ alkyl, OH, aryloxy, alkoxy, arylalkoxy, NH₂, NH(alkyl),         N(alkyl) (alkyl), or —C₁-C₆ alkyl-CO₂—C₁-C₆ alkyl, each of which         is optionally substituted with 1, 2, 3, 4, or 5 groups that are         independently alkyl, alkoxy, CO₂H, —CO₂-alkyl, thioalkoxy,         halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkanoyl, NO₂, CN,         alkoxycarbonyl, or aminocarbonyl;

-   X is selected from the group consisting of —C₁-C₆ alkylidenyl     optionally optionally substituted with 1, 2, or 3 methyl groups; and     —NR₄₋₆—; or     -   R₄ and R₄₋₆ combine to form —(CH₂)_(n10)—, wherein         -   n₁₀ is 1, 2, 3, or 4;

-   Z is selected from the group consisting of a bond; SO₂; SO; S; and     C(O);

-   Y is selected from the group consisting of H; C₁-C₄ haloalkyl; C₅-C₆     heterocycloalkyl; C₆-C₁₀ aryl; OH; —N(Y₁) (Y₂); C₁-C₁₀ alkyl     optionally substituted with 1 thru 3 substituents which can be the     same or different and are selected from the group consisting of     halogen, hydroxy, alkoxy, thioalkoxy, and haloalkoxy; C₃-C₈     cycloalkyl optionally substituted with 1, 2, or 3 groups     independently selected from C₁-C₃ alkyl, and halogen; alkoxy; aryl     optionally substituted with halogen, alkyl, alkoxy, CN or NO₂;     arylalkyl optionally substituted with halogen, alkyl, alkoxy, CN or     NO₂; wherein     -   Y₁ and Y₂ are the same or different and are H; C₁-C₁₀ alkyl         optionally substituted with 1, 2, or 3 substituents selected         from the group consisting of halogen, C₁-C₄ alkoxy, C₃-C₈         cycloalkyl, and OH; C₂-C₆ alkenyl; C₂-C₆ alkanoyl; phenyl;         —SO₂—C₁-C₄ alkyl; phenyl C₁-C₄ alkyl; or C₃-C₈ cycloalkyl C₁-C₄         alkyl; or     -   Y₁, Y₂ and the nitrogen to which they are attached form a ring         selected from the group consisting of piperazinyl, piperidinyl,         morpholinyl, and pyrolidinyl, wherein each ring is optionally         substituted with 1, 2, 3, or 4 groups that are independently         C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, or halogen;

-   R₁ is —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl), or     -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, OH, ═O, —SH, —C≡N, —CF₃,         —C₁-C₃ alkoxy, amino, mono- or dialkylamino, —N(R)C(O)R′—,         —OC(═O)-amino and —OC(═O)-mono- or dialkylamino, or     -   C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionally         substituted with 1, 2, or 3 groups independently selected from         halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or         dialkylamino, or     -   aryl, heteroaryl, heterocyclyl, —C₁-C₆ alkyl-aryl, —C₁-C₆         alkyl-heteroaryl, or —C₁-C₆ alkyl-heterocyclyl, where the ring         portions of each are optionally substituted with 1, 2, 3, or 4         groups independently selected from halogen, —OH, —SH, —C≡N,         —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′, or —N(R)SO₂R′,         —C(═O)—(C₁-C₄)alkyl, —SO₂-amino, —SO₂-mono or dialkylamino,         —C(═O)-amino, —C(═O)-mono or dialkylamino, —SO₂—(C₁-C₄)alkyl, or         -   —C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups             which are independently a halogen, or         -   C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3             groups independently selected from halogen, —OH, —SH, —C≡N,             —CF₃, C₁-C₃ alkoxy, amino, —C₁-C₆ alkyl and mono- or             dialkylamino, or         -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups             independently selected from halogen, —OH, —SH, —C≡N, —CF₃,             —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃             alkyl, or         -   C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally             substituted with 1, 2, or 3 groups independently selected             from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino,             C₁-C₆ alkyl and mono- or dialkylamino; and         -   the heterocyclyl group is optionally further substituted             with oxo;

-   R and R′ independently are hydrogen or C₁-C₁₀ alkyl;

-   R₂ is selected from the group consisting of H; C₁-C₆ alkyl,     optionally substituted with 1, 2, or 3 substituents that are     independently selected from the group consisting of C₁-C₃ alkyl,     halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b);     wherein R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl; —(CH₂)₀₋₄-aryl;     —(CH₂)₀₋₄-heteroaryl; C₂-C₆ alkenyl; C₂-C₆ alkynyl;     —CONR_(N-2)R_(N-3); —SO₂NR_(N-2)R_(N-3); —CO₂H; and —CO₂—(C₁-C₄     alkyl);

-   R₃ is selected from the group consisting of H; C₁-C₆ alkyl,     optionally substituted with 1, 2, or 3 substituents independently     selected from the group consisting of C₁-C₃ alkyl, halogen, —OH,     —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b); —(CH₂)₀₋₄-aryl;     —(CH₂)₀₋₄-heteroaryl; C₂-C₆ alkenyl; C₂-C₆ alkynyl;     —CO—NR_(N-2)R_(N-3); —SO₂—NR_(N-2)R_(N-3); —CO₂H; and —CO—O—(C₁-C₄     alkyl); or

-   R₂, R₃ and the carbon to which they are attached form a carbocycle     of three thru seven carbon atoms, wherein one carbon atom is     optionally replaced by a group selected from —O—, —S—, —SO₂—, or     —NR_(N-2)—;

-   R_(C) is selected from the group consisting of C₁-C₁₀ alkyl     optionally substituted with 1, 2, or 3 groups independently selected     from the group consisting of R₂₀₅, —OC═ONR₂₃₅R₂₄₀, —S(═O)₀₋₂(C₁-C₆     alkyl), —SH, —NR₂₃₅C═ONR₂₃₅R₂₄₀, —C═ONR₂₃₅R₂₄₀, and     —S(═O)₂NR₂₃₅R₂₄₀; —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl wherein the     cycloalkyl is optionally substituted with 1, 2, or 3 groups     independently selected from the group consisting of R₂₀₅, —CO₂H, and     —CO₂—(C₁-C₄ alkyl); —(CR₂₄₅R₂₅₀)₀₋₄-aryl;     —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl; —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl;     —(CR₂₄₅R₂₅₀)₀₋₄-aryl-heteroaryl;     —(CR₂₄₅R₂₅₀)₀₋₄-aryl-heterocycloalkyl; —(CR₂₄₅R₂₅₀)₀₋₄-aryl-aryl;     —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-aryl;     —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heterocycloalkyl;     —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heteroaryl;     —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-heteroaryl;     —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-heterocycloalkyl;     —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-aryl; —[C(R₂₅₅)     (R₂₆₀)]₁₋₃—CO—N—(R₂₅₅)₂; —CH(aryl)₂; —CH(heteroaryl)₂;     —CH(heterocycloalkyl)₂; —CH(aryl)(heteroaryl); cyclopentyl,     cyclohexyl, or cycloheptyl ring fused to aryl, heteroaryl, or     heterocycloalkyl wherein one carbon of the cyclopentyl, cyclohexyl,     or cycloheptyl is optionally replaced with NH, NR₂₁₅, O, or     S(═O)₀₋₂, and wherein the cyclopentyl, cyclohexyl, or cycloheptyl     group can be optionally substituted with 1 or 2 groups that are     independently R₂₀₅ or ═O; —CO—NR₂₃₅R₂₄₀; —SO₂—(C₁-C₄ alkyl); C₂-C₁₀     alkenyl optionally substituted with 1, 2, or 3 R₂₀₅ groups; C₂-C₁₀     alkynyl optionally substituted with 1, 2, or 3 R₂₀₅ groups;     —(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH)—(CH₂)₀₋₁-aryl;     —(CH₂)₀₋₁—CHR_(C-6)—(CH₂)₀₋₁-heteroaryl; —CH(-aryl or     -heteroaryl)-CO—O(C₁-C₄ alkyl); —CH(—CH₂—OH)—CH(OH)-phenyl-NO₂;     (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-OH; —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂; —H;     and —(CH₂)₀₋₆—C(═NR₂₃₅) (NR₂₃₅R₂₄₀); wherein     -   each aryl is optionally substituted with 1, 2, or 3 R₂₀₀;     -   each heteroaryl is optionally substituted with 1, 2, 3, or 4         R₂₀₀;     -   each heterocycloalkyl is optionally substituted with 1, 2, 3, or         4 R₂₁₀;     -   R₂₀₀ at each occurrence is independently selected from the group         consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3         R₂₀₅ groups; OH; —NO₂; halogen; —CO₂H; C≡N;         —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl);         —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl); —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl);         —(CH₂)₀₋₄—CO—(C₃-C₇ cycloalkyl); —(CH₂)₀₋₄—CO-aryl;         —(CH₂)₀₋₄—CO-heteroaryl; —(CH₂)₀₋₄—CO-heterocycloalkyl;         —(CH₂)₀₋₄—CO₂R₂₁₅; —(CH₂)₀₋₄—SO₂—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—SO—(C₁-C₈         alkyl); —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl); —(CH₂)₀₋₄—SO₂—(C₃-C₇         cycloalkyl); —(CH₂)₀₋₄—N(H or R₂₁₅)—CO₂R₂₁₅; —(CH₂)₀₋₄—N(H or         R₂₁₅)—CO—N(R₂₁₅)₂; —(CH₂)₀₋₄—N—CS—N(R₂₁₅)₂; —(CH₂)₀₋₄—N(—H or         R₂₁₅)—CO—R₂₂₀; —(CH₂)₀₋₄—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—O—CO—(C₁-C₆         alkyl); —(CH₂)₀₋₄ —O—P(O)—(OR₂₄₀)₂; —(CH₂)₀₋₄—O—CO—N(R₂₁₅)₂;         —(CH₂)₀₋₄—O—CS—N(R₂₁₅)₂; —(CH₂)₀₋₄—O—(R₂₁₅)₂;         —(CH₂)₀₋₄—O—(R₂₁₅)₂—COOH; —(CH₂)₀₋₄—S—(R₂₁₅)₂;         —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally substituted with 1, 2, 3, or         5-F); C₃-C₇ cycloalkyl; C₂-C₆ alkenyl optionally substituted         with 1 or 2 R₂₀₅ groups; C₂-C₆ alkynyl optionally substituted         with 1 or 2 R₂₀₅ groups; —(CH₂)₀₋₄—N(H or R₂₁₅)—SO₂—R₂₂₀; and         —(CH₂)₀₋₄—C₃-C₇ cycloalkyl;         -   wherein each aryl group at each occurrence is optionally             substituted with 1, 2, or 3 groups that are independently             R₂₀₅, R₂₁₀ or C₁-C₆ alkyl substituted with 1, 2, or 3 groups             that are independently R₂₀₅ or R₂₁₀;         -   wherein each heterocycloalkyl group at each occurrence is             optionally substituted with 1, 2, or 3 groups that are             independently R₂₁₀;         -   wherein each heteroaryl group at each occurrence is             optionally substituted with 1, 2, or 3 groups that are             independently R₂₀₅, R₂₁₀, or C₁-C₆ alkyl substituted with 1,             2, or 3 groups that are independently R₂₀₅ or R₂₁₀;     -   R₂₀₅ at each occurrence is independently selected from the group         consisting of C₁-C₆ alkyl, halogen, —OH, —O-phenyl, —SH, —C≡N,         —CF₃, C₁-C₆ alkoxy, NH₂, NH(C₁-C₆ alkyl), and N—(C₁-C₆         alkyl)(C₁-C₆ alkyl);     -   R₂₁₀ at each occurrence is independently selected from the group         consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3         R₂₀₅ groups; C₂-C₆ alkenyl optionally substituted with 1, 2, or         3 R₂₀₅ groups; C₂-C₆ alkynyl optionally substituted with 1, 2,         or 3 R₂₀₅ groups; halogen; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy;         —NR₂₂₀R₂₂₅; OH; C≡N; C₃-C₇ cycloalkyl optionally substituted         with 1, 2, or 3 R₂₀₅ groups; —CO—(C₁-C₄ alkyl); SO₂—NR₂₃₅R₂₄₀;         —CO—NR₂₃₅R₂₄₀; —SO₂—(C₁-C₄ alkyl); and ═O; wherein     -   R₂₁₅ at each occurrence is independently selected from the group         consisting of C₁-C₆ alkyl, —(CH₂)₀₋₂-(aryl), C₂-C₆ alkenyl,         C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, and —(CH₂)₀₋₂-(heteroaryl),         —(CH₂)₀₋₂-(heterocycloalkyl); wherein the aryl group at each         occurrence is optionally substituted with 1, 2, or 3 groups that         are independently R₂₀₅ or R₂₁₀; wherein the heterocycloalkyl         group at each occurrence is optionally substituted with 1, 2, or         3 R₂₁₀; wherein each heteroaryl group at each occurrence is         optionally substituted with 1, 2, or 3 R₂₁₀;     -   R₂₂₀ and R₂₂₅ at each occurrence are independently selected from         the group consisting of —H, —C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl,         amino C₁-C₆ alkyl; halo C₁-C₆ alkyl; —C₃-C₇ cycloalkyl, —(C₁-C₂         alkyl)-(C₃-C₇ cycloalkyl), —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),         —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁-C₆ alkyl chain with one         double bond and one triple bond, -aryl, -heteroaryl, and         -heterocycloalkyl; wherein the aryl group at each occurrence is         optionally substituted with 1, 2, or 3 R₂₇₀ groups, wherein     -   R₂₇₀ at each occurrence is independently R₂₀₅, C₁-C₆ alkyl         optionally substituted with 1, 2, or 3 R₂₀₅ groups; C₂-C₆         alkenyl optionally substituted with 1, 2, or 3 R₂₀₅ groups;         C₂-C₆ alkynyl optionally substituted with 1, 2, or 3 R₂₀₅         groups; halogen; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; NR₂₃₅R₂₄₀; OH;         C≡N; C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3         R₂₀₅ groups; —CO—(C₁-C₄ alkyl); SO₂—NR₂₃₅R₂₄₀; —CO—NR₂₃₅R₂₄₀;         —SO₂—(C₁-C₄ alkyl); and ═O; wherein the heterocycloalkyl group         at each occurrence is optionally substituted with 1, 2, or 3         R₂₀₅ groups; wherein each heteroaryl group at each occurrence is         optionally substituted with 1, 2, or 3 R₂₀₅ groups;     -   R₂₃₅ and R₂₄₀ at each occurrence are independently H, or C₁-C₆         alkyl;     -   R₂₄₅ and R₂₅₀ at each occurrence are independently selected from         the group consisting of H, C₁-C₄ alkyl, C₁-C₄ hydroxyalkyl,         C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, —(CH₂)₀₋₄—C₃-C₇ cycloalkyl,         C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl C₁-C₄ alkyl, heteroaryl C₁-C₄         alkyl, and phenyl; or     -   R₂₄₅ and R₂₅₀ are taken together with the carbon to which they         are attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon         atoms, optionally where one carbon atom is replaced by a         heteroatom selected from the group consisting of —O—, —S—,         —SO₂—, and —NR₂₂₀—;     -   R₂₅₅ and R₂₆₀ at each occurrence are independently selected from         the group consisting of H; C₁-C₆ alkyl optionally substituted         with 1, 2, or 3 R₂₀₅ groups; C₂-C₆ alkenyl optionally         substituted with 1, 2, or 3 R₂₀₅ groups; C₂-C₆ alkynyl         optionally substituted with 1, 2, or 3 R₂₀₅ groups;         —(CH₂)₁₂—S(O)₀₋₂—(C₁-C₆ alkyl); —(CH₂)₀₋₄—C₃-C₇ cycloalkyl         optionally substituted with 1, 2, or 3 R₂₀₅ groups; —(C₁-C₄         alkyl)-aryl; —(C₁-C₄ alkyl)-heteroaryl; —(C₁-C₄         alkyl)-heterocycloalkyl; -aryl; -heteroaryl; -heterocycloalkyl;         (CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-aryl; —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heteroaryl;         and; —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heterocycloalkyl; wherein         -   R₂₆₅ at each occurrence is independently —O—, —S— or             —N(C₁-C₆ alkyl)-;         -   each aryl or phenyl is optionally substituted with 1, 2, or             3 groups that are independently R₂₀₅, R₂₁₀, or C₁-C₆ alkyl             substituted with 1, 2, or 3 groups that are independently             R₂₀₅ or R₂₁₀;         -   each heteroaryl is optionally substituted with 1, 2, 3, or 4             R₂₀₀, each heterocycloalkyl is optionally substituted with             1, 2, 3, or 4 R₂₁₀;

-   R₁₀₀ and R′₁₀₀ independently represent aryl, heteroaryl,     heterocyclyl, -aryl-W-aryl, -aryl-W-heteroaryl,     -aryl-W-heterocyclyl, -heteroaryl-W-aryl, -heteroaryl-W-heteroaryl,     -heteroaryl-W-heterocyclyl, -heterocyclyl-W-aryl,     -heterocyclyl-w-heteroaryl, -heterocyclyl-W-heterocyclyl,     —CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-aryl,     —CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-heterocyclyl or —CH     [(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-heteroaryl, where the ring portions of     each are optionally substituted with 1, 2, or 3 groups independently     selected from     -   —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,         —(CH₂)₀₋₄—O—P(═O)(OR)(OR′), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,         —(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),         —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),         —(CH₂)₀₋₄—CO—(CH₂)₀₋₄ (C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R₁₁₀,         —(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀,         —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₄₀,         —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅,         —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl),         —(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇ cycloalkyl),         —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀, —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂,         —(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅,         —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₋₄—O—CO—(C₁-C₆         alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂, —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂,         —(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀),         —(CH₂)₀₋₄—O—R₁₅₀′—COOH, —(CH₂)₀₋₄—S—(R₁₅₀),         —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, —(CH₂)₀₋₄—C₃-C₇ cycloalkyl,         (C₂-C₁₀)alkenyl, and (C₂-C₁₀)alkynyl, or

-   R₁₀₀ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 R₁₁₅     groups, or

-   R₁₀₀ is —(C₁-C₆ alkyl)-O—C₁-C₆ alkyl) or —(C₁-C₆ alkyl)-S—(C₁-C₆     alkyl), each of which is optionally substituted with 1, 2, or 3 R₁₁₅     groups, or

-   R₁₀₀ is C₃-C₈ cycloalkyl optionally substituted with 1, 2, or 3 R₁₁₅     groups;

-   W is —(CH₂)₀₋₄—O——S(O)₀₋₂—, —N(R₁₃₅)—, —CR(OH)— or —C(O)—;

-   R₁₀₂ and R₁₀₂′ independently are hydrogen, or     -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups that         are independently halogen, aryl or —R₁₁₀;

-   R₁₀₅ and R′₁₀₅ independently represent —H, —R₁₁₀, —R₁₂₀, C₃-C₇     cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), —(C₁-C₆     alkyl)-O—(C₁-C₃ alkyl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆ alkyl     chain with one double bond and one triple bond, or     -   C₁-C₆ alkyl optionally substituted with —OH or —NH₂; or,     -   C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, or

-   R₁₀₅ and R′₁₀₅ together with the atom to which they are attached     form a 3 to 7 membered carbocylic ring, where one member is     optionally a heteratom selected from —O—, —S(O)₀₋₂—, —N(R₁₃₅)—, the     ring being optionally substituted with 1, 2 or 3 independently     selected R₁₄₀ groups;

-   R₁₁₅ at each occurrence is independently halogen, —OH, —CO₂R₁₀₂,     —C₁-C₆ thioalkoxy, —CO₂-phenyl, —NR₁₀₅R′₁₃₅, —SO₂—(C₁-C₈ alkyl),     —C(═O)R₁₈₀, R₁₈₀, —CONR₁₀₅R′₁₀₅, —SO₂NR₁₀₅R′₁₀₅, —NH—CO—(C₁-C₆     alkyl), —NH—C(═O)—OH, —NH—C(═O)—OR, —NH—C(═O)—O-phenyl,     —O—C(═O)—(C₁-C₆ alkyl), —O—C(═O)-amino, —O—C(═O)-mono- or     dialkylamino, —O—C(═O)-phenyl, —O—(C₁-C₆ alkyl)—CO₂H, —NH—SO₂—(C₁-C₆     alkyl), C₁-C₆ alkoxy or C₁-C₆ haloalkoxy;

-   R₁₃₅ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,     —(CH₂)₀₋₂-(aryl), —(CH₂)₀₋₂-(heteroaryl), or     —(CH₂)₀₋₂-(heterocyclyl);

-   R₁₄₀ is heterocyclyl optionally substituted with 1, 2, 3, or 4     groups independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,     halogen, hydroxy, cyano, nitro, amino, mono (C₁-C₆)alkylamino,     di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl,     C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl,     mono(C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl,     and ═O;

-   R₁₄₅ is C₁-C₆ alkyl or CF₃;

-   R₁₅₀ is hydrogen, C₃-C₇ cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇     cycloalkyl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl with one     double bond and one triple bond, —R₁₁₀, —R₁₂₀, or     -   C₁-C₆ alkyl optionally substituted with 1, 2, 3, or 4 groups         independently selected from —OH, —NH₂, C₁-C₃ alkoxy, R₁₁₀, and         halogen;

-   R₁₅₀′ is C₃-C₇ cycloalkyl, —(C₁-C₃ alkyl)-(C₃-C₇ cycloalkyl), C₂-C₆     alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl with one double bond and one     triple bond, —R₁₁₀, —R₁₂₀, or     -   C₁-C₆ alkyl optionally substituted with 1, 2, 3, or 4 groups         independently selected from —OH, —NH₂, C₁-C₃ alkoxy, R₁₁₀, and         halogen;

-   R₁₅₅ is C₃-C₇ cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), C₂-C₆     alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl with one double bond and one     triple bond, —R₁₁₀, —R₁₂₀, or     -   C₁-C₆ alkyl optionally substituted with 1, 2, 3, or 4 groups         independently selected from —OH, —NH₂, C₁-C₃ alkoxy, and         halogen;

-   R₁₈₀ is selected from morpholinyl, thiomorpholinyl, piperazinyl,     piperidinyl, homomorpholinyl, homothiomorpholinyl,     homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide,     pyrrolinyl and pyrrolidinyl, each of which is optionally substituted     with 1, 2, 3, or 4 groups independently selected from C₁-C₆ alkyl,     C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino,     mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆     alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl, mono     (C₁-C₆)alkylamino (C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl, and     ═O;

-   R₁₁₀ is aryl optionally substituted with 1 or 2 R₁₂₅ groups;

-   R₁₂₅ at each occurrence is independently halogen, amino, mono- or     dialkylamino, —OH, —C≡N, —SO₂—NH₂, —SO₂—NH—C₁-C₆ alkyl, —SO₂—N(C₁-C₆     alkyl)₂, —SO₂—(C₁-C₄ alkyl), —CO—NH₂, —CO—NH—C₁-C₆ alkyl, or     —CO—N(C₁-C₆ alkyl)₂, or     -   C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is         optionally substituted with 1, 2, or 3 groups that are         independently selected from C₁-C₃ alkyl, halogen, —OH, —SH,         —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- and dialkylamino, or     -   C₁-C₆ alkoxy optionally substituted with one, two or three of         halogen;

-   R₁₂₀ is heteroaryl, which is optionally substituted with 1 or 2 R₁₂₅     groups; and

-   R₁₃₀ is heterocyclyl optionally substituted with 1 or 2 R₁₂₅ groups.

The invention also provides compounds of the formula I:

-   and pharmaceutically acceptable salts thereof, wherein R₁, R₂, R₃,     and R_(C) are as defined for formula (AA), and -   R_(N) is —C(═O)—(CRR′)₀₋₆R₁₀₀, —C(═O)—(CRR′)₁₋₆—O—R′₁₀₀,     —C(═O)—(CRR′)₁₋₆—S—R′₁₀₀, —C(═O)—(CRR′)₁₋₆—C(═O)—R₁₀₀,     —C(═O)—(CRR′)₁₋₆—SO₂—R₁₀₀, —C(═O)—(CRR′)₁₋₆—NR₁₀₀—R′₁₀₀, or -   R_(N) is

-   -   wherein

-   R₄ is selected from the group consisting of H; NH₂;     —NH—(CH₂)_(n6)—R₄₋₁; —NHR₈; —NR₅₀C(O)R₅; C₁-C₄ alkyl-NHC(O)R₅;     —(CH₂)₀₋₄R₈; —O—C₁-C₄ alkanoyl; OH; C₆-C₁₀ aryloxy optionally     substituted with 1, 2, or 3 groups that are independently halogen,     C₁-C₄ alkyl, —CO₂H, —C(O)—C₁-C₄ alkoxy, or C₁-C₄ alkoxy; C₁-C₆     alkoxy; aryl C₁-C₄ alkoxy; —NR₅₀CO₂R₅₁; —C₁-C₄ alkyl-NR₅₀CO₂R₅₁;     —C≡N; —CF₃; —CF₂—CF₃; —C≡CH; —CH₂—CH═CH₂; —(CH₂)₁₋₄—R₄₋₁;     —(CH₂)₁₋₄—NH—R₄₋₁; —O—(CH₂)_(n6)—R₄₋₁; —S—(CH₂)_(n6)—R₄₋₁;     —(CH₂)₀₋₄—NHC(O)—(CH₂)₀₋₆—R₅₂; —(CH₂)₀₋₄—R₅₃—(CH₂)₀₋₄—R₅₄;     -   wherein         -   n₆ is 0, 1, 2, or 3;         -   n₇ is 0, 1, 2, or 3;     -   R₄₋₁ is selected from the group consisting of —SO₂—(C₁-C₈         alkyl), —SO—(C₁-C₈ alkyl), —S—(C₁-C₈ alkyl), —S—CO—(C₁-C₆         alkyl), —SO₂—NR₄₋₂R₄₋₃; —CO—C₁-C₂ alkyl; —CO—NR₄₋₃R₄₋₄;     -   R₄₋₂ and R₄₋₃ are independently H, C₁-C₃ alkyl, or C₃-C₆         cycloalkyl;     -   R₄₋₄ is alkyl, arylalkyl, alkanoyl, or arylalkanoyl;     -   R₄₋₆ is —H or C₁-C₆ alkyl;     -   R₅ is selected from the group consisting of C₃-C₇ cycloalkyl;         C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that         are independently halogen, —NR₆R₇, C₁-C₄ alkoxy, C₅-C₆         heterocycloalkyl, C₅-C₆ heteroaryl, C₆-C₁₀ aryl, C₃-C₇         cycloalkyl C₁-C₄ alkyl, —S—C₁-C₄ alkyl, —SO₂—C₁-C₄ alkyl, —CO₂H,         —CONR₆R₇, —CO₂—C₁-C₄ alkyl, C₆-C₁₀ aryloxy; heteroaryl         optionally substituted with 1, 2, or 3 groups that are         independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₁-C₄         haloalkyl, or OH; heterocycloalkyl optionally substituted with         1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄         alkoxy, halogen, or C₂-C₄ alkanoyl; aryl optionally substituted         with 1, 2, 3, or 4 groups that are independently halogen, OH,         C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₁-C₄ haloalkyl; and —NR₆R₇;         wherein         -   R₆ and R₇ are independently selected from the group             consisting of H, C₁-C₆ alkyl, C₂-C₆ alkanoyl, phenyl,             —SO₂—C₁-C₄ alkyl, phenyl C₁-C₄ alkyl;     -   R₈ is selected from the group consisting of —SO₂-heteroaryl,         —SO₂-aryl, —SO₂-heterocycloalkyl, —SO₂—C₁-C₁₀ alkyl, —C(O)NHR₉,         heterocycloalkyl, —S—C₁-C₆ alkyl, —S—C₂-C₄ alkanoyl, wherein         -   R₉ is aryl C₁-C₄ alkyl, C₁-C₆ alkyl, or H; R₅₀ is H or C₁-C₆             alkyl;     -   R₅₁ is selected from the group consisting of aryl C₁-C₄ alkyl;         C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that         are independently halogen, cyano, heteroaryl, —NR₆R₇,         —C(O)NR₆R₇, C₃-C₇ cycloalkyl, or —C₁-C₄ alkoxy; heterocycloalkyl         optionally substituted with 1 or 2 groups that are independently         C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₂-C₄ alkanoyl, aryl C₁-C₄         alkyl, and —SO₂ C₁-C₄ alkyl; alkenyl; alkynyl; heteroaryl         optionally substituted with 1, 2, or 3 groups that are         independently OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, NH₂,         NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl)(C₁-C₆ alkyl); heteroarylalkyl         optionally substituted with 1, 2, or 3 groups that are         independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, NH₂, NH(C₁-C₆         alkyl) or N(C₁-C₆ alkyl)(C₁-C₆ alkyl); aryl; heterocycloalkyl;         C₃-C₈ cycloalkyl; and cycloalkylalkyl; wherein the aryl;         heterocycloalkyl, C₃-C₈ cycloalkyl, and cycloalkylalkyl groups         are optionally substituted with 1, 2, 3, 4 or 5 groups that are         independently halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆         alkanoyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, hydroxy, C₁-C₆         hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ thioalkoxy, C₁-C₆         thioalkoxy C₁-C₆ alkyl, or C₁-C₆ alkoxy C₁-C₆ alkoxy;     -   R₅₂ is heterocycloalkyl, heteroaryl, aryl, cycloalkyl,         —S(O)₀₋₂—C₁-C₆ alkyl, CO₂H, —C(O)NH₂, —C(O)NH(alkyl),         —C(O)N(alkyl) (alkyl), —CO₂-alkyl, —NHS(O)₀₋₂—C₁-C₆ alkyl,         —N(alkyl)S(O)₀₋₂—C₁-C₆ alkyl, —S(O)₀₋₂-heteroaryl,         —S(O)₀₋₂-aryl, —NH(arylalkyl), —N(alkyl) (arylalkyl),         thioalkoxy, or alkoxy, each of which is optionally substituted         with 1, 2, 3, 4, or 5 groups that are independently alkyl,         alkoxy, thioalkoxy, halogen, haloalkyl, haloalkoxy, alkanoyl,         NO₂, CN, alkoxycarbonyl, or aminocarbonyl;     -   R₅₃ is absent, —O—, —C(O)—, —NH—, —N(alkyl)-, —NH—S(O)₀₋₂—,         —N(alkyl)-S(O)₀₋₂—, —S(O)₀₋₂—NH—, —S(O)O₀₋₂—N(alkyl)-,         —NH—C(S)—, or —N(alkyl)-C(S)—;     -   R₅₄ is heteroaryl, aryl, arylalkyl, heterocycloalkyl, CO₂H,         —CO₂-alkyl, —C(O)NH(alkyl), —C(O)N(alkyl) (alkyl), —C(O)NH₂,         C₁-C₈ alkyl, OH, aryloxy, alkoxy, arylalkoxy, NH₂, NH(alkyl),         N(alkyl) (alkyl), or —C₁-C₆ alkyl-CO₂—C₁-C₆ alkyl, each of which         is optionally substituted with 1, 2, 3, 4, or 5 groups that are         independently alkyl, alkoxy, CO₂H, —CO₂-alkyl, thioalkoxy,         halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkanoyl, NO₂, CN,         alkoxycarbonyl, or aminocarbonyl;

-   X is selected from the group consisting of —C₁-C₆ alkylidenyl     optionally optionally substituted with 1, 2, or 3 methyl groups; and     —NR₄₋₆—; or     -   R₄ and R₄₋₆ combine to form —(CH₂)_(n10)—, wherein n₁₀ is 1, 2,         3, or 4;

-   Z is selected from the group consisting of a bond; SO₂; SO; S; and     C(O);

-   Y is selected from the group consisting of H; C₁-C₄ haloalkyl; C₅-C₆     heterocycloalkyl; C₆-C₁₀ aryl; OH; —N(Y₁)(Y₂); C₁-C₁₀ alkyl     optionally substituted with 1 thru 3 substituents which can be the     same or different and are selected from the group consisting of     halogen, hydroxy, alkoxy, thioalkoxy, and haloalkoxy; C₃-C₈     cycloalkyl optionally substituted with 1, 2, or 3 groups     independently selected from C₁-C₃ alkyl, and halogen; alkoxy; aryl     optionally substituted with halogen, alkyl, alkoxy, CN or NO₂;     arylalkyl optionally substituted with halogen, alkyl, alkoxy, CN or     NO₂; wherein     -   Y₁ and Y₂ are the same or different and are H; C₁-C₁₀ alkyl         optionally substituted with 1, 2, or 3 substituents selected         from the group consisting of halogen, C₁-C₄ alkoxy, C₃-C₈         cycloalkyl, and OH; C₂-C₆ alkenyl; C₂-C₆ alkanoyl; phenyl;         —SO₂—C₁-C₄ alkyl; phenyl C₁-C₄ alkyl; or C₃-C₈ cycloalkyl C₁-C₄         alkyl; or     -   Y₁, Y₂ and the nitrogen to which they are attached form a ring         selected from the group consisting of piperazinyl, piperidinyl,         morpholinyl, and pyrolidinyl, wherein each ring is optionally         substituted with 1, 2, 3, or 4 groups that are independently         C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, or halogen;

-   R₁₀₀ and R′₁₀₀ independently represent aryl, heteroaryl,     heterocyclyl, -aryl-W-aryl, -aryl-W-heteroaryl,     -aryl-W-heterocyclyl, -heteroaryl-W-aryl, -heteroaryl-W-heteroaryl,     -heteroaryl-W-heterocyclyl, -heterocyclyl-W-aryl,     -heterocyclyl-W-heteroaryl, -heterocyclyl-W-heterocyclyl,     —CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-aryl,     —CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-heterocyclyl or —CH     [(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-heteroaryl, where the ring portions of     each are optionally substituted with 1, 2, or 3 groups independently     selected from     -   —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,         —(CH₂)₀₋₄—O—P(═O) (OR) (OR′), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,         —(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),         —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),         —(CH₂)₀₋₄—CO—(CH₂)₀₋₄ (C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R₁₁₀,         —(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀,         —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₄₀,         —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅,         —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂ (C₁-C₁₂ alkyl),         —(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇ cycloalkyl),         —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀, —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂,         —(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅,         —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₋₄—O—CO—(C₁-C₆         alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂, —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂,         —(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀),         —(CH₂)₀₋₄—O—R₁₅₀—COOH, —(CH₂)₀₋₄—S—(R₁₅₀),         —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, —(CH₂)₀₋₄—C₃-C₇ cycloalkyl,         (C₂-C₁₀)alkenyl, and (C₂-C₁₀)alkynyl, or

-   R₁₀₀ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 R₁₁₅     groups, or

-   R₁₀₀ is —(C₁-C₆ alkyl)-O—C₁-C₆ alkyl) or —(C₁-C₆ alkyl)-S—(C₁-C₆     alkyl), each of which is optionally substituted with 1, 2, or 3 R₁₁₅     groups, or

-   R₁₀₀ is C₃-C₈ cycloalkyl optionally substituted with 1, 2, or 3 R₁₁₅     groups;

-   W is —(CH₂)₀₋₄—, —O—, —S(O)₀₋₂—, —N(R₁₃₅)—, —CR(OH)— or —C(O)—;

-   R₁₀₂ and R₁₀₂′ independently are hydrogen, or     -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups that         are independently halogen, aryl or —R₁₁₀;

-   R₁₀₅ and R′₁₀₅ independently represent —H, —R₁₁₀, —R₁₂₀, C₃-C₇     cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), —(C₁-C₆     alkyl)-O—(C₁-C₃ alkyl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆ alkyl     chain with one double bond and one triple bond, or     -   C₁-C₆ alkyl optionally substituted with —OH or —NH₂; or,     -   C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, or

-   R₁₀₅ and R′₁₀₅ together with the atom to which they are attached     form a 3 to 7 membered carbocylic ring, where one member is     optionally a heteratom selected from —O—, —S(O)₀₋₂—, —N(R₁₃₅)—, the     ring being optionally substituted with 1, 2 or 3 independently     selected R₁₄₀ groups;

-   R₁₁₅ at each occurrence is independently halogen, —OH, —CO₂R₁₀₂,     —C₁-C₆ thioalkoxy, —CO₂-phenyl, —NR₁₀₅R′₁₃₅, —SO₂—(C₁-C₈ alkyl),     —C(═O)R₁₈₀, R₁₈₀, —CONR₁₀₅R′₁₀₅, —SO₂NR₁₀₅R′₁₀₅, —NH—CO—(C₁-C₆     alkyl), —NH—C(═O)—OH, —NH—C(═O)—OR, —NH—C(═O)—O-phenyl,     —O—C(═O)—(C₁-C₆ alkyl), —O—C(═O)-amino, —O—C(═O)-mono- or     dialkylamino, —O—C(═O)-phenyl, —O—(C₁-C₆ alkyl)-CO₂H, —NH—SO₂—(C₁-C₆     alkyl), C₁-C₆ alkoxy or C₁-C₆ haloalkoxy;

-   R₁₃₅ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,     —(CH₂)₀₋₂-(aryl), —(CH₂)₀₋₂-(heteroaryl), or     —(CH₂)₀₋₂-(heterocyclyl);

-   R₁₄₀ is heterocyclyl optionally substituted with 1, 2, 3, or 4     groups independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,     halogen, hydroxy, cyano, nitro, amino, mono (C₁-C₆)alkylamino,     di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl,     C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl,     mono(C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl,     and ═O;

-   R₁₄₅ is C₁-C₆ alkyl or CF₃;

-   R₁₅₀ is hydrogen, C₃-C₇ cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇     cycloalkyl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl with one     double bond and one triple bond, —R₁₁₀, —R₁₂₀, or     -   C₁-C₆ alkyl optionally substituted with 1, 2, 3, or 4 groups         independently selected from —OH, —NH₂, C₁-C₃ alkoxy, R₁₁₀, and         halogen;

-   R₁₅₀′ is C₃-C₇ cycloalkyl, —(C₁-C₃ alkyl)-(C₃-C₇ cycloalkyl), C₂-C₆     alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl with one double bond and one     triple bond, —R₁₁₀, —R₁₂₀, or     -   C₁-C₆ alkyl optionally substituted with 1, 2, 3, or 4 groups         independently selected from —OH, —NH₂, C₁-C₃ alkoxy, R₁₁₀, and         halogen;

-   R₁₅₅ is C₃-C₇ cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), C₂-C₆     alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl with one double bond and one     triple bond, —R₁₁₀, —R₁₂₀, or     -   C₁-C₆ alkyl optionally substituted with 1, 2, 3, or 4 groups         independently selected from —OH, —NH₂, C₁-C₃ alkoxy, and         halogen;

-   R₁₈₀ is selected from morpholinyl, thiomorpholinyl, piperazinyl,     piperidinyl, homomorpholinyl, homothiomorpholinyl,     homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide,     pyrrolinyl and pyrrolidinyl, each of which is optionally substituted     with 1, 2, 3, or 4 groups independently selected from C₁-C₆ alkyl,     C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino,     mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆     alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl, mono     (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl, and     ═O;

-   R₁₁₀ is aryl optionally substituted with 1 or 2 R₁₂₅ groups;

-   R₁₂₅ at each occurrence is independently halogen, amino, mono- or     dialkylamino, —OH, —C≡N, —SO₂—NH₂, —SO₂—NH—C₁-C₆ alkyl, —SO₂—N(C₁-C₆     alkyl)₂, —SO₂—(C₁-C₄ alkyl), —CO—NH₂, —CO—NH—C₁-C₆ alkyl, or     —CO—N(C₁-C₆ alkyl)₂, or     -   C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is         optionally substituted with 1, 2, or 3 groups that are         independently selected from C₁-C₃ alkyl, halogen, —OH, —SH,         —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- and dialkylamino, or     -   C₁-C₆ alkoxy optionally substituted with one, two or three of         halogen;

-   R₁₂₀ is heteroaryl, which is optionally substituted with 1 or 2 R₁₂₅     groups; and

-   R₁₃₀ is heterocyclyl optionally substituted with 1 or 2 R₁₂₅ groups.

The invention also provides compounds of the formula X:

and pharmaceutically acceptable salts thereof, wherein R₁, R₂, R₃, R_(N) and R_(C) are as defined for formula (I).

The invention also provides methods of generating compounds of formula (Y) from the compounds of formulae (AA), (I) or (X):

wherein R₁, R₂, R₃, R_(N) and R_(C) are as defined for formula (I). The generation of compounds of formula (Y) from compounds of formulae (AA), (I) or (X) can occur in vivo or in vitro. Compounds of formula Y are useful for treating and/or preventing Alzheimer's disease.

The invention also provides processes for converting compounds of formula AA, I or X to the compounds of formula Y. The conversion and/or generation of compounds of formula Y involves contacting the compounds of formula I and/or X with an aqueous medium. The conversion can occur in vitro or in vivo.

The invention also provides methods for the treatment or prevention of Alzheimer's disease, mild cognitive impairment Down's syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, other degenerative dementias, dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer's disease compriseing administration of a therapeutically effective amount of a compound or salt of formula AA, I or X, to a patient in need thereof.

Preferably, the patient is a human.

More preferably, the disease is Alzheimer's disease.

More preferably, the disease is dementia.

The invention also provides pharmaceutical compositions comprising a compound or salt of formula AA, I or X and at least one pharmaceutically acceptable carrier, solvent, adjuvant or diluent.

The invention also provides the use of a compound or salt according to formula AA, I or X for the manufacture of a medicament.

The invention also provides the use of a compound or salt of formula (AA), formula (I) or formula (X) for the treatment or prevention of Alzheimer's disease, mild cognitive impairment Down's syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, other degenerative dementias, dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, or diffuse Lewy body type of Alzheimer's disease.

The invention also provides compounds, pharmaceutical compositions, kits, and methods for inhibiting beta-secretase-mediated cleavage of amyloid precursor protein (APP). More particularly, the compounds, compositions, and methods of the invention are effective to inhibit the production of A-beta peptide and to treat or prevent any human or veterinary disease or condition associated with a pathological form of A-beta peptide.

The invention also provides methods of preparing the compounds of the invention and the intermediates used in those methods.

The compounds, compositions, and methods of the invention are useful for treating humans who have Alzheimer's Disease (AD), for helping prevent or delay the onset of AD, for treating patients with mild cognitive impairment (MCI), and preventing or delaying the onset of AD in those patients who would otherwise be expected to progress from MCI to AD, for treating Down's syndrome, for treating Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type, for treating cerebral beta-amyloid angiopathy and preventing its potential consequences such as single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, for treating dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, and diffuse Lewy body type AD, and for treating frontotemporal dementias with parkinsonism (FTDP).

The compounds of formula Y possess beta-secretase inhibitory activity. The inhibitory activities of the compounds of the invention is readily demonstrated, for example, using one or more of the assays described herein or known in the art.

Unless the substituents for a particular formula are expressly defined for that formula, they are understood to carry the definitions set forth in connection with the preceding formula to which the particular formula makes reference.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the invention provides compounds of formulae (AA), (I) and (X) that are useful in the treatment and prevention of Alzheimer's disease. These compounds can be viewed as prodrugs of the active compounds of Formula Y since they generate the active compound both in vivo and in vitro.

The compounds of formula AA, I and X undergo acyl group migration of the R_(N) group when in contact with water, as depicted in Scheme I. The migration associated with compounds of formula (I) is referred to herein as “N-acyl migration.” The migration associated with compounds of formula (X) is referred to herein as “O-acyl migration.”

The migrations depicted in SCHEME 1 can occur either in vitro or in vivo and occur when the compounds are contacted with aqueous media, including water itself. The aqueous medium can be neutral, acidic or basic. It is preferred that the media have a pH of about 2 to about 10, more preferably, about 3 to about 7. The amount of water required for the migration is not critical. A catalytic amount of aqueous media will suffice to cause the migration. Aqueous buffer solutions as well as gastric fluid are satisfactory media for the migration to occur.

The products of the rearrangements of the compounds of formula AA, formula I and/or formula X are the compounds of formula (Y). The substituents R₁, R₂, R₃, R_(N) and R_(C) in the compounds (Y) are as defined above for compounds of formula (I).

Preferred compounds of formula AA include those of formula AA-1, i.e., compounds of formula AA wherein

-   R₁ is aryl, heteroaryl, heterocyclyl, —C₁-C₆ alkyl-aryl, —C₁-C₆     alkyl-heteroaryl, or —C₁-C₆ alkyl-heterocyclyl, where the ring     portions of each are optionally substituted with 1, 2, 3, or 4     groups independently selected from halogen, —OH, —SH, —C≡N, —NO₂,     —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′, or —N(R)SO₂R′, —C(═O)—(C₁-C₄)alkyl,     —SO₂-amino, —SO₂-mono or dialkylamino, —C(═O)-amino, —C(═O)-mono or     dialkylamino, —SO₂—(C₁-C₄) alkyl, or     -   C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups which         are independently selected from halogen, or     -   C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃         alkoxy, amino, —C₁-C₆ alkyl and mono- or dialkylamino, or     -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, —OH, —SH, —C≡N, —CF₃,         —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, or     -   C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally         substituted with 1, 2, or 3 groups independently selected from         halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl         and mono- or dialkylamino; and the heterocyclyl group is         optionally further substituted with oxo.

Preferred compounds of formula AA-1 also include those wherein

-   R₁ is —C₁-C₆ alkyl-aryl, —C₁-C₆ alkyl-heteroaryl, or —C₁-C₆     alkyl-heterocyclyl, where the ring portions of each are optionally     substituted with 1, 2, 3, or 4 groups independently selected from     halogen, —OH, —SH, —C≡N, —NO₂, —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′, or     —N(R)SO₂R′, —C(═O)—(C₁-C₄)alkyl, —SO₂-amino, —SO₂-mono or     dialkylamino, —C(═O)-amino, —C(═O)-mono or dialkylamino,     —SO₂—(C₁-C₄) alkyl, or     -   C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups which         are independently selected from halogen, or     -   C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃         alkoxy, amino, —C₁-C₆ alkyl and mono- or dialkylamino, or     -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, —OH, —SH, —C≡N, —CF₃,         —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, or     -   C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally         substituted with 1, 2, or 3 groups independently selected from         halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl         and mono- or dialkylamino; and the heterocyclyl group is         optionally further substituted with oxo.

Preferred compounds of formula AA-1 further include those wherein

-   R₁ is —(CH₂)-aryl, —(CH₂)-heteroaryl, or —(CH₂)-heterocyclyl, where     the ring portions of each are optionally substituted with 1, 2, 3,     or 4 groups independently selected from halogen, —OH, —SH, —C≡N,     —NO₂, —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′, or —N(R)SO₂R,     —C(═O)—(C₁-C₄)alkyl, —SO₂-amino, —SO₂-mono or dialkylamino,     —C(═O)-amino, —C(═O)-mono or dialkylamino, —SO₂—(C₁-C₄) alkyl, or     -   C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups which         are independently selected from halogen, or     -   C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃         alkoxy, amino, —C₁-C₆ alkyl and mono- or dialkylamino, or     -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, —OH, —SH, —C≡N, —CF₃,         —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, or     -   C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally         substituted with 1, 2, or 3 groups independently selected from         halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl         and mono- or dialkylamino; and the heterocyclyl group is         optionally further substituted with oxo.

Preferred compounds of formula AA-1 also include those wherein

-   R₁ is —CH₂-phenyl or —CH₂-pyridinyl where the ring portions of each     are optionally substituted with 1, 2, 3, or 4 groups independently     selected from halogen, C₁-C₄ alkoxy, hydroxy, —NO₂, and     -   C₁-C₄ alkyl optionally substituted with 1, 2, or 3 substituents         independently selected from halogen, OH, SH, NH₂, NH(C₁-C₆         alkyl), N-(C₁-C₆ alkyl) (C₁-C₆ alkyl), C≡N, CF₃.

Preferred compounds of formula AA-1 further include those wherein

-   R₁ is —CH₂-phenyl or —CH₂-pyridinyl where the phenyl or pyridinyl     rings are each optionally substituted with 1 or 2 groups     independently selected from halogen, C₁-C₂ alkyl, C₁-C₂ alkoxy,     hydroxy, —CF₃, and —NO₂.

Preferred compounds of formula AA-1 include those wherein

-   R₁ is —CH₂-phenyl where the phenyl ring is optionally substituted     with 2 groups independently selected from halogen, C₁-C₂ alkyl,     C₁-C₂ alkoxy, hydroxy, and —NO₂.

Preferred compounds of formula AA-1 also include those wherein R₁ is benzyl, or 3,5-difluorobenzyl.

Preferred compounds of formula AA and AA-1 include those of formula AA-2, i.e., compounds of formula AA or AA-1 wherein

-   R₂ and R₃ are independently selected from H or C₁-C₆ alkyl     optionally substituted with 1, 2, or 3 substituents selected from     the group consisting of C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃,     C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b).

Preferred compounds of formula AA-2 include those wherein

-   R_(C) is selected from the group consisting of C₁-C₁₀ alkyl     optionally substituted with 1, 2, or 3 groups independently selected     from the group consisting of R₂₀₅, —OC═ONR₂₃₅R₂₄₀, —S(═O)₀₋₂(C₁-C₆     alkyl), —SH, —NR₂₃₅C═ONR₂₃₅R₂₄₀, —C═ONR₂₃₅R₂₄₀, and     —S(═O)₂NR₂₃₅R₂₄₀; —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl wherein the     cycloalkyl is optionally substituted with 1, 2, or 3 groups     independently selected from the group consisting of R₂₀₅, —CO₂H, and     —CO₂—(C₁-C₄ alkyl); —(CR₂₄₅R₂₅₀)₀₋₄-aryl;     —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl; —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl;     —[C(R₂₅₅) (R₂₆₀)]₁₃—CO—N—(R₂₅₅)₂; —CH(aryl)₂; —CH(heteroaryl)₂;     —CH(heterocycloalkyl)₂; —CH (aryl) (heteroaryl); —CO—NR₂₃₅R₂₄₀;     —(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH)—(CH₂)₀₋₁-aryl;     —(CH₂)₀₋₁—CHR_(C-6)—(CH₂)₀₋₁-heteroaryl; —CH(-aryl or     -heteroaryl)-CO—O(C₁-C₄ alkyl); —CH(—CH₂—OH)—CH(OH)-phenyl-NO₂;     (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-OH; —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂; —H;     and —(CH₂)₀₋₆—C(═NR₂₃₅) (NR₂₃₅R₂₄₀); wherein     -   each aryl is optionally substituted with 1, 2, or 3 R₂₀₀;     -   each heteroaryl is optionally substituted with 1, 2, 3, or 4         R₂₀₀;     -   each heterocycloalkyl is optionally substituted with 1, 2, 3, or         4 R₂₁₀;     -   R₂₀₀ at each occurrence is independently selected from the group         consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3         R₂₀₅ groups; OH; —NO₂; halogen; —CO₂H; C≡N;         —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl);         —(CH₂)₀₋₄—CO₂R₂₁₅; and —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally         substituted with 1, 2, 3, or 5-F);         -   wherein each aryl group at each occurrence is optionally             substituted with 1, 2, or 3 groups that are independently             R₂₀₅, R₂₁₀ or C₁-C₆ alkyl substituted with 1, 2, or 3 groups             that are independently R₂₀₅ or R₂₁₀;         -   wherein each heterocycloalkyl group at each occurrence is             optionally substituted with 1, 2, or 3 groups that are             independently R₂₁₀;         -   wherein each heteroaryl group at each occurrence is             optionally substituted with 1, 2, or 3 groups that are             independently R₂₀₅, R₂₁₀, or C₁-C₆ alkyl substituted with 1,             2, or 3 groups that are independently R₂₀₅ or R₂₁₀;     -   R₂₀₅ at each occurrence is independently selected from the group         consisting of C₁-C₆ alkyl, halogen, —OH, —O-phenyl, —SH, —C≡N,         —CF₃, C₁-C₆ alkoxy, NH₂, NH(C₁-C₆ alkyl), and N-(C₁-C₆ alkyl)         (C₁-C₆ alkyl);     -   R₂₁₀ at each occurrence is independently selected from the group         consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3         R₂₀₅ groups; halogen; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy;         —NR₂₂₀R₂₂₅; OH; C≡N; C₃-C₇ cycloalkyl optionally substituted         with 1, 2, or 3 R₂₀₅ groups; —CO—(C₁-C₄ alkyl); SO₂NR₂₃₅R₂₄₀;         —CO—NR₂₃₅R₂₄₀; —SO₂—(C₁-C₄ alkyl); and ═O; wherein     -   R₂₁₅ at each occurrence is independently selected from the group         consisting of C₁-C₆ alkyl, —(CH₂)₀₋₂—(aryl), C₃-C₇ cycloalkyl,         and —(CH₂)₀₋₂-(heteroaryl), —(CH₂)₀₋₂-(heterocycloalkyl);         wherein the aryl group at each occurrence is optionally         substituted with 1, 2, or 3 groups that are independently R₂₀₅         or R₂₁₀; wherein the heterocycloalkyl group at each occurrence         is optionally substituted with 1, 2, or 3 R₂₁₀; wherein each         heteroaryl group at each occurrence is optionally substituted         with 1, 2, or 3 R₂₁₀;     -   R₂₂₀ and R₂₂₅ at each occurrence are independently selected from         the group consisting of —H, —C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl,         amino C₁-C₆ alkyl; halo C₁-C₆ alkyl; —C₃-C₇ cycloalkyl, —(C₁-C₆         alkyl)-O—(C₁-C₃ alkyl), -aryl, -heteroaryl, and         -heterocycloalkyl; wherein the aryl group at each occurrence is         optionally substituted with 1, 2, or 3 R₂₇₀ groups, each         heteroaryl is optionally substituted with 1, 2, 3, or 4 R₂₀₀,         each heterocycloalkyl is optionally substituted with 1, 2, 3, or         4 R₂₁₀ wherein     -   R₂₇₀ at each occurrence is independently R₂₀₅, C₁-C₆ alkyl         optionally substituted with 1, 2, or 3 R₂₀₅ groups; halogen;         C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; NR₂₃₅R₂₄₀; OH; C≡N; —CO—(C₁-C₄         alkyl); and ═O; wherein the heterocycloalkyl group at each         occurrence is optionally substituted with 1, 2, or 3 R₂₀₅         groups; wherein each heteroaryl group at each occurrence is         optionally substituted with 1, 2, or 3 R₂₀₅ groups;     -   R₂₃₅ and R₂₄₀ at each occurrence are independently H, or C₁-C₆         alkyl;     -   R₂₄₅ and R₂₅₀ at each occurrence are independently selected from         the group consisting of H, C₁-C₄ alkyl, C₁-C₄ hydroxyalkyl,         C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, or     -   R₂₄₅ and R₂₅₀ are taken together with the carbon to which they         are attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon         atoms, wherein the carbocycle is optionally substituted with 1         or 2 groups that are independently OH, methyl, Cl, F, OCH₃, CF₃,         NO₂, or CN;     -   R₂₅₅ and R₂₆₀ at each occurrence are independently selected from         the group consisting of H; C₁-C₆ alkyl optionally substituted         with 1, 2, or 3 R₂₀₅ groups; —(CH₂)₀₋₄—C₃-C₇ cycloalkyl         optionally substituted with 1, 2, or 3 R₂₀₅ groups; —(C₁-C₄         alkyl)-aryl; —(C₁-C₄ alkyl)-heteroaryl; —(C₁-C₄         alkyl)-heterocycloalkyl; aryl; heteroaryl; heterocycloalkyl;         —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-aryl;         —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heteroaryl; and;         —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heterocycloalkyl; wherein         -   R₂₆₅ at each occurrence is independently —O—, —S— or             —N(C₁-C₆ alkyl)-;         -   each aryl or phenyl is optionally substituted with 1, 2, or             3 groups that are independently R₂₀₅, R₂₁₀, or C₁-C₆ alkyl             substituted with 1, 2, or 3 groups that are independently             R₂₀₅ or R₂₁₀.

Preferred compounds of formula AA-2 include those wherein:

-   R_(C) is —(CR₂₄₅R₂₅₀)₀₋₄-aryl, or —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl,     wherein aryl and heteroaryl are optionally substituted with 1, 2, or     3 R₂₀₀ groups.

Preferred compounds of formula AA-2 also include compounds wherein

-   R_(C) is —(CR₂₄₅R₂₅₀)-aryl, or —(CR₂₄₅R₂₅₀)-heteroaryl wherein each     aryl and heteroaryl is optionally substituted with 1, 2, or 3 R₂₀₀     groups.

Preferred compounds of formula AA-2 also include compounds wherein

-   -   R_(C) is —(CH₂)-aryl, or —(CH₂)-heteroaryl, wherein         -   each aryl and heteroaryl is optionally substituted with 1,             2, or 3 groups selected from OH, —NO₂, halogen, —CO₂H, C≡N,             —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), and             —(CH₂)₀₋₄—SO₂—NR₂₂₀R₂₂₅.

Preferred compounds of formula AA-2 also include compounds wherein

-   R_(C) is —(CH₂)-aryl, wherein aryl is optionally substituted with 1,     2, or 3 groups selected from OH, —NO₂, halogen, —CO₂H, and C≡N.

Preferred compounds of formula AA-2 also include compounds wherein

-   R_(C) is —(CH₂)-phenyl, wherein phenyl is optionally substituted     with 1, 2, or 3 groups selected from OH, —NO₂, halogen, —CO₂H, and     C≡N.

Preferred compounds of formula AA-2 also include compounds wherein R_(C) is benzyl.

Other preferred compounds of formulas AA, AA-1 and AA-2 include compounds of formula AA-3, i.e., those of formulas AA, AA-1 or AA-2 wherein

-   one of R_(N) and R_(N)′ is hydrogen and the other is:

-   -   wherein

-   R₄ is NH₂; —NH—(CH₂)_(n6)—R₄₋₁; —NHR₈; —NR₅₀C(O)R₅; or —NR₅₀CO₂R₅₁;     -   wherein         -   n₆ is 0, 1, 2, or 3;         -   n₇ is 0, 1, 2, or 3;     -   R₄₋₁ is selected from the group consisting of —SO₂—(C₁-C₈         alkyl), —SO—(C₁-C₈ alkyl), —S—(C₁-C₈ alkyl), —S—CO—(C₁-C₆         alkyl), —SO₂—NR₄₋₂R₄₋₃; —CO—C₁-C₂ alkyl; —CO—NR₄₋₃R₄₋₄;     -   R₄₋₂ and R₄₋₃ are independently H, C₁-C₃ alkyl, or C₃-C₆         cycloalkyl;     -   R₄₋₄ is alkyl, phenylalkyl, C₂-C₄ alkanoyl, or phenylalkanoyl;

-   R₅ is cyclopropyl; cyclobutyl; cyclopentyl; and cyclohexyl; wherein     each cycloalkyl group is optionally substituted with one or two     groups that are C₁-C₆ alkyl, more preferably C₁-C₂ alkyl, C₁-C₆     alkoxy, more preferably C₁-C₂ alkoxy, CF₃, OH, NH₂, NH(C₁-C₆ alkyl),     N(C₁-C₆ alkyl) (C₁-C₆ alkyl), halogen, CN, or NO₂; or the cycloalkyl     group is substituted with 1 or 2 groups that are independently CF₃,     Cl, F, methyl, ethyl or cyano; C₁-C₆ alkyl optionally substituted     with 1, 2, or 3 groups that are independently halogen, —NR₆R₇, C₁-C₄     alkoxy, C₅-C₆ heterocycloalkyl, C₅-C₆ heteroaryl, phenyl, C₃-C₇     cycloalkyl, —S—C₁-C₄ alkyl, —SO₂—C₁-C₄ alkyl, —CO₂H, —CONR₆R₇,     —CO₂—C₁-C₄ alkyl, or phenyloxy; heteroaryl optionally substituted     with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄     alkoxy, halogen, C₁-C₄ haloalkyl, or OH; heterocycloalkyl optionally     substituted with 1, 2, or 3 groups that are independently C₁-C₄     alkyl, C₁-C₄ alkoxy, halogen, or C₂-C₄ alkanoyl; phenyl optionally     substituted with 1, 2, 3, or 4 groups that are independently     halogen, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₁-C₄ haloalkyl; and     —NR₆R₇; wherein     -   R₆ and R₇ are independently selected from the group consisting         of H, C₁-C₆ alkyl, C₂-C₆ alkanoyl, phenyl, —SO₂—C₁-C₄ alkyl, and         phenyl C₁-C₄ alkyl;     -   R₈ is selected from the group consisting of —SO₂-heteroaryl         optionally substituted with 1 or 2 groups that are independently         C₁-C₄ alkyl or halogen;, —SO₂-aryl, —SO₂-heterocycloalkyl,         —C(O)NHR₉, heterocycloalkyl, —S—C₂-C₄ alkanoyl, wherein         -   R₉ is phenyl C₁-C₄ alkyl, C₁-C₆ alkyl, or H; R₅₀ is H or             C₁-C₆ alkyl;     -   R₅₁ is selected from the group consisting of phenyl C₁-C₄ alkyl;         C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that         are independently halogen, cyano, —NR₆R₇, —C(O)NR₆R₇, C₃-C₇ or         —C₁-C₄ alkoxy; heterocycloalkyl optionally substituted with 1 or         2 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, C₂-C₄ alkanoyl, phenyl C₁-C₄ alkyl, and —SO₂ C₁-C₄         alkyl; heterocycloalkylalkyl optionally substituted with 1 or 2         groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, C₂-C₄ alkanoyl, phenyl C₁-C₄ alkyl, and —SO₂ C₁-C₄         alkyl; alkenyl; alkynyl; heteroaryl optionally substituted with         1, 2, or 3 groups that are independently OH, C₁-C₄ alkyl, C₁-C₄         alkoxy, halogen, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆         alkyl); heteroarylalkyl optionally substituted with 1, 2, or 3         groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl);         phenyl; C₃-C₈ cycloalkyl, and cycloalkylalkyl, wherein the         phenyl; C₃-C₈ cycloalkyl, and cycloalkylalkyl groups are         optionally substituted with 1, 2, 3, 4 or 5 groups that are         independently halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆         alkanoyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, hydroxy, C₁-C₆         hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ thioalkoxy, C₁-C₆         thioalkoxy C₁-C₆ alkyl, or C₁-C₆ alkoxy C₁-C₆ alkoxy.

Preferred compounds of formula AA-3 include compounds wherein

-   -   one of R_(N) and R_(N)′ is hydrogen and the other is

-   -   wherein

-   X is C₁-C₄ alkylidenyl optionally substituted with 1, 2, or 3 methyl     groups; or —NR₄₋₆—; or     -   R₄ and R₄₋₆ combine to form —(CH₂)_(n10)—, wherein         -   n₁₀ is 1, 2, 3, or 4;

-   Z is selected from a bond; SO₂; SO; S; and C(O);

-   Y is selected from H; C₁-C₄ haloalkyl; C₅-C₆ heterocycloalkyl     containing at least one N, O, or S; phenyl; OH; —N(Y₁)(Y₂); C₁-C₁₀     alkyl optionally substituted with 1 thru 3 substituents which can be     the same or different and are selected from halogen, hydroxy,     alkoxy, thioalkoxy, and haloalkoxy; C₃-C₈ cycloalkyl optionally     substituted with 1, 2, or 3 groups independently selected from C₁-C₃     alkyl, and halogen; alkoxy; phenyl optionally substituted with     halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CN or NO₂; phenyl C₁-C₄ alkyl     optionally substituted with halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CN     or NO₂; wherein     -   Y₁ and Y₂ are the same or different and are H; C₁-C₁₀ alkyl         optionally substituted with 1, 2, or 3 substituents selected         from the group consisting of halogen, C₁-C₄ alkoxy, C₃-C₈         cycloalkyl, and OH; C₂-C₆ alkenyl; C₂-C₆ alkanoyl; phenyl;         —SO₂—C₁-C₄ alkyl; phenyl C₁-C₄ alkyl; and C₃-C₈ cycloalkyl C₁-C₄         alkyl; or     -   —N(Y₁) (Y₂) forms a ring selected from piperazinyl, piperidinyl,         morpholinyl, and pyrolidinyl, wherein each ring is optionally         substituted with 1, 2, 3, or 4 groups that are independently         C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, or halogen.

Preferred compounds of formula AA-3 include compounds wherein

-   X is C₁-C₄ alkylidenyl optionally optionally substituted with 1, 2,     or 3 methyl groups; -   Z is selected from SO₂; SO; S; and C(O); -   Y is selected from H; C₁-C₄ haloalkyl; C₅-C₆ heterocycloalkyl     containing at least one N, O, or S; phenyl; OH; —N(Y₁) (Y₂); C₁-C₁₀     alkyl optionally substituted with 1 thru 3 substituents which can be     the same or different and are selected from the group consisting of     halogen, hydroxy, alkoxy, thioalkoxy, and haloalkoxy; C₃-C₈     cycloalkyl optionally substituted with 1, 2, or 3 groups     independently selected from C₁-C₃ alkyl, and halogen; alkoxy; phenyl     optionally substituted with halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CN     or NO₂; phenyl C₁-C₄ alkyl optionally substituted with halogen,     C₁-C₄ alkyl, C₁-C₄ alkoxy, CN or NO₂; wherein     -   Y₁ and Y₂ are the same or different and are H; C₁-C₆ alkyl         optionally substituted with 1, 2, or 3 substituents selected         from the group consisting of halogen, C₁-C₄ alkoxy, C₃-C₈         cycloalkyl, and OH; C₂-C₆ alkenyl; C₂-C₆ alkanoyl; phenyl;         —SO₂—C₁-C₄ alkyl; phenyl C₁-C₄ alkyl; or C₃-C₈ cycloalkyl C₁-C₄         alkyl; or     -   —N(Y₁) (Y₂) forms a ring selected from piperazinyl, piperidinyl,         morpholinyl, and pyrolidinyl, wherein each ring is optionally         substituted with 1, 2, 3, or 4 groups that are independently         C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, or halogen.

Preferred compounds of formula AA-3 include compounds one of R_(N) and R_(N)′ is hydrogen and the other is:

-   -   wherein R₄ is NH₂; —NH—(CH₂)_(n6)—R₄₋₁; —NHR₈; —NR₅₀C(O)R₅; or         —NR₅₀CO₂R₅₁ wherein         -   n₆ is 0, 1, 2, or 3;         -   n₇ is 0, 1, 2, or 3;     -   R₄₋₁ is selected from the group consisting of —SO₂—(C₁-C₈         alkyl), —SO—(C₁-C₈ alkyl), —S—(C₁-C₈ alkyl), —S—CO—(C₁-C₆         alkyl), —SO₂—NR₄₋₂R₄₋₃; —CO—C₁-C₂ alkyl; —CO—NR₄₋₃R₄₋₄;     -   R₄₋₂ and R₄₋₃ are independently H, C₁-C₃ alkyl, or C₃-C₆         cycloalkyl;     -   R₄₋₄ is alkyl, phenylalkyl, C₂-C₄ alkanoyl, or phenylalkanoyl;     -   R₅ is cyclopropyl; cyclobutyl; cyclopentyl; or cyclohexyl;         wherein each cycloalkyl group is optionally substituted with one         or two groups that are C₁-C₆ alkyl, more preferably C₁-C₂ alkyl,         C₁-C₆ alkoxy, more preferably C₁-C₂ alkoxy, CF₃, OH, NH₂,         NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl) (C₁-C₆ alkyl), halogen, CN, or         NO₂; or the cycloalkyl group is substituted with 1 or 2 groups         that are independently CF₃, Cl, F, methyl, ethyl or cyano; C₁-C₆         alkyl optionally substituted with 1, 2, or 3 groups that are         independently halogen, —NR₆R₇, C₁-C₄ alkoxy, C₅-C₆         heterocycloalkyl, C₅-C₆ heteroaryl, phenyl, C₃-C₇ cycloalkyl,         —S—C₁-C₄ alkyl, —SO₂—C₁-C₄ alkyl, —CO₂H, —CONR₆R₇, —CO₂—C₁-C₄         alkyl, or phenyloxy; heteroaryl optionally substituted with 1,         2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, C₁-C₄ haloalkyl, or OH; heterocycloalkyl optionally         substituted with 1, 2, or 3 groups that are independently C₁-C₄         alkyl, C₁-C₄ alkoxy, halogen, or C₂-C₄ alkanoyl; phenyl         optionally substituted with 1, 2, 3, or 4 groups that are         independently halogen, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₁-C₄         haloalkyl; and —NR₆R₇; wherein     -   R₆ and R₇ are independently selected from the group consisting         of H, C₁-C₆ alkyl, C₂-C₆ alkanoyl, phenyl, —SO₂—C₁-C₄ alkyl, and         phenyl C₁-C₄ alkyl;     -   R₈ is selected from the group consisting of —SO₂-heteroaryl         optionally substituted with 1 or 2 groups that are independently         C₁-C₄ alkyl or halogen;, —SO₂-aryl, —SO₂-heterocycloalkyl,         —C(O)NHR₉, heterocycloalkyl, —S—C₂-C₄ alkanoyl, wherein         -   R₉ is phenyl C₁-C₄ alkyl, C₁-C₆ alkyl, or H; R₅₀ is H or             C₁-C₆ alkyl; and     -   R₅₁ is selected from the group consisting of phenyl C₁-C₄ alkyl;         C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that         are independently halogen, cyano, —NR₆R₇, —C(O)NR₆R₇, C₃-C₇ or         —C₁-C₄ alkoxy; heterocycloalkyl optionally substituted with 1 or         2 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, C₂-C₄ alkanoyl, phenyl C₁-C₄ alkyl, and —SO₂ C₁-C₄         alkyl; heterocycloalkylalkyl optionally substituted with 1 or 2         groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, C₂-C₄ alkanoyl, phenyl C₁-C₄ alkyl, and —SO₂ C₁-C₄         alkyl; alkenyl; alkynyl; heteroaryl optionally substituted with         1, 2, or 3 groups that are independently OH, C₁-C₄ alkyl, C₁-C₄         alkoxy, halogen, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆         alkyl); heteroarylalkyl optionally substituted with 1, 2, or 3         groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl);         phenyl; C₃-C₈ cycloalkyl, and cycloalkylalkyl, wherein the         phenyl; C₃-C₈ cycloalkyl, and cycloalkylalkyl groups are         optionally substituted with 1, 2, 3, 4 or 5 groups that are         independently halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆         alkanoyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, hydroxy, C₁-C₆         hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ thioalkoxy, C₁-C₆         thioalkoxy C₁-C₆ alkyl, or C₁-C₆ alkoxy C₁-C₆ alkoxy; and

-   Y is C₁-C₁₀ alkyl optionally substituted with 1 thru 3 substituents     which can be the same or different and are selected from halogen,     hydroxy, alkoxy, thioalkoxy, and haloalkoxy.

Preferred compounds of formula AA-3 further include compounds wherein

-   R_(C) is C₁-C₈ alkyl optionally substituted with 1, 2, or 3 groups     independently selected from the group consisting of R₂₀₅,     —OC═ONR₂₃₅R₂₄₀, —S(═O)₀₋₂(C₁-C₆ alkyl), —SH, —C═ONR₂₃₅R₂₄₀, and     —S(═O)₂NR₂₃₅R₂₄₀; —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl wherein the     cycloalkyl is optionally substituted with 1, 2, or 3 groups     independently selected from the group consisting of R₂₀₅, —CO₂H, and     —CO₂—(C₁-C₄ alkyl); —(CR₂₄₅R₂₅₀)₀₋₄-phenyl;     —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl; —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl;     —(CH₂)₀₋₁—CH((CH₂)₀₋₄—OH)—(CH₂)₀₋₁-phenyl;     —(CH₂)₀₋₁—CHR_(C-6)—(CH₂)₀₋₁-heteroaryl;     —CH(—CH₂—OH)—CH(OH)-phenyl-NO₂; (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-OH; or     —(CH₂)₀₋₆—C(═NR₂₃₅) (NR₂₃₅R₂₄₀); wherein     -   each aryl is optionally substituted with 1, 2, or 3 R₂₀₀;     -   each heteroaryl is optionally substituted with 1, 2, 3, or 4         R₂₀₀;     -   each heterocycloalkyl is optionally substituted with 1, 2, 3, or         4 R₂₁₀;     -   R₂₀₀ at each occurrence is independently C₁-C₆ alkyl optionally         substituted with 1, 2, or 3 R₂₀₅ groups; OH; —NO₂; halogen;         —CO₂H; C≡N; —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl);         —(CH₂)₀₋₄—CO₂R₂₁₅; or —(CH₂)_(0-—) ₄—O—(C₁-C₆ alkyl optionally         substituted with 1, 2, 3, or 5-F);     -   R₂₀₅ at each occurrence is independently C₁-C₆ alkyl, halogen,         —OH, —O-phenyl, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, NH₂, NH(C₁-C₆         alkyl), or N—(C₁-C₆ alkyl) (C₀-C₆ alkyl);     -   R₂₁₀ at each occurrence is independently C₁-C₆ alkyl optionally         substituted with 1, 2, or 3 R₂₀₅ groups; halogen; C₁-C₆ alkoxy;         C₁-C₆ haloalkoxy; —NR₂₂₀R₂₂₅; OH; C≡N; C₃-C₇ cycloalkyl         optionally substituted with 1, 2, or 3 R₂₀₅ groups; —CO—(C₁-C₄         alkyl); SO₂NR₂₃₅R₂₄₀; —CO—NR₂₃₅R₂₄₀; —SO₂—(C₁-C₄ alkyl); and ═O;         wherein     -   R₂₁₅ at each occurrence is independently C₁-C₆ alkyl,         —(CH₂)₀₋₂-(phenyl), C₃₋C₇ cycloalkyl, and         —(CH₂)₀₋₂-(heteroaryl), —(CH₂)₀₋₂-(heterocycloalkyl); wherein         the phenyl group at each occurrence is optionally substituted         with 1, 2, or 3 groups that are independently R₂₀₅ or R₂₁₀;         wherein the heterocycloalkyl group at each occurrence is         optionally substituted with 1, 2, or 3 R₂₁₀; wherein each         heteroaryl group at each occurrence is optionally substituted         with 1, 2, or 3 R_(210;)     -   R₂₂₀ and R₂₂₅ at each occurrence are independently —H, —C₁-C₆         alkyl, hydroxy C₁-C₆ alkyl, halo C₁-C₆ alkyl; —C₃-C₇ cycloalkyl,         and —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl);     -   R₂₃₅ and R₂₄₀ at each occurrence are independently H, or C₁-C₆         alkyl;     -   R₂₄₅ and R₂₅₀ at each occurrence are independently H, C₁-C₄         alkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, or     -   R₂₄₅ and R₂₅₀ are taken together with the carbon to which they         are attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon         atoms.

Preferred compounds of formula AA-3 include compounds wherein

-   R₁ is benzyl which is optionally substituted with 1, 2, 3, or 4     groups independently selected from halogen, C₁-C₄ alkoxy, hydroxy,     and C₁-C₄ alkyl optionally substituted with 1, 2, or 3 substituents     halogen, OH, SH, NH₂, NH(C₁-C₆ alkyl), N-(C₁-C₆ alkyl)     (C₁-C₆-alkyl), C≡N, CF₃; -   R₂ and R₃ are independently selected from H or C₁-C₄ alkyl     optionally substituted with 1 substituent selected from halogen,     —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, NH₂, NH(C₁-C₆ alkyl), and     NH(C₁-C₆ alkyl) (C₁-C₆ alkyl); -   R_(C) is C₁-C₈ alkyl optionally substituted with 1, 2, or 3 groups     independently selected from R₂₀₅, —SH, —C═ONR₂₃₅R₂₄₀, and     —S(═O)₂NR₂₃₅R₂₄₀; —(CH₂)₀₋₃—(C₃-C₆) cycloalkyl wherein the     cycloalkyl is optionally substituted with 1, 2, or 3 groups     independently selected from R₂₀₅, —CO₂H, and —CO₂—(C₁-C₄ alkyl);     —(CR₂₄₅R₂₅₀)₀₋₄-phenyl optionally substituted with 1, 2, or 3 R₂₀₀;     —(CR₂₄₅R₂₅₀)₀₋₃-pyridyl; —(CR₂₄₅R₂₅₀)₀₋₃-pyridazinyl;     —(CR₂₄₅R₂₅₀)₀₋₃-pyrimidinyl; —(CR₂₄₅R₂₅₀)₀₋₃-pyrazinyl;     —(CR₂₄₅R₂₅₀)₀₋₃-furyl; —(CR₂₄₅R₂₅₀)₀₋₃-indolyl; —(CR₂₄₅R₂₅₀)     O₃-thienyl; —(CR₂₄₅R₂₅₀)₀₋₃-pyrrolyl; —(CR₂₄₅R₂₅₀)₀₋₃-pyrazolyl;     (CR₂₄₅R₂₅₀)₀₋₃-benzoxazolyl; —(CR₂₄₅R₂₅₀)₀₋₃-imidazolyl; each of the     above heteroaryl groups is optionally substituted with 1, 2, 3, or 4     R₂₀₀; —(CR₂₄₅R₂₅₀)₀₋₃-imidazolidinyl;     (CR₂₄₅R₂₅₀)₀₋₃-tetrahydrofuryl; (CR₂₄₅R₂₅₀)₀₋₃-tetrahydropyranyl;     (CR₂₄₅R₂₅₀)₀₋₃-piperazinyl; (CR₂₄₅R₂₅₀)₀₋₃-pyrrolidinyl;     (CR₂₄₅R₂₅₀)₀₋₃-piperidinyl; (CR₂₄₅R₂₅₀)₀₋₃-indolinyl; each of the     above heterocycloalkyl groups is optionally substituted with 1, 2,     3, or 4 R₂₁₀; (CH₂)₀₋₁—CH((CH₂)₀₋₄—OH)—(CH₂)₀₋₁-phenyl;     —(CH₂)₀₋₁—CH(C₁-C₄ hydroxyalkyl)-(CH₂)₀₋₁-pyridyl;     -   R₂₀₀ at each occurrence is independently C₁-C₆ alkyl optionally         substituted with 1, 2, or 3 R₂₀₅ groups; OH; —NO₂; halogen;         —CO₂H; C≡N; —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—CO—(C₁-C₈ alkyl);         —(CH₂)₀₋₄—CO₂R₂₁₅; and —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally         substituted with 1, 2, 3, or 5-F);     -   R₂₀₅ at each occurrence is independently C₁-C₆ alkyl, halogen,         —OH, —O-phenyl, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, NH₂, NH(C₁-C₆         alkyl), and N-(C₁-C₆ alkyl)(C₁-C₆ alkyl);     -   R₂₁₀ at each occurrence is independently C₁-C₆ alkyl optionally         substituted with 1 or 2 R₂₀₅ groups; halogen; C₃-C₄ alkoxy;         C₁-C₄ haloalkoxy; —NR₂₂₀R₂₂₅; OH; C≡N; C₃-C₇ cycloalkyl         optionally substituted with 1 or 2 R₂₀₅ groups; —CO—(C₁-C₄         alkyl); SO₂NR₂₃₅R₂₄₀; —CO—NR₂₃₅R₂₄₀; —SO₂—(C₁-C₄ alkyl); and ═O;         wherein     -   R₂₁₅ at each occurrence is independently C₁-C₆ alkyl,         —(CH₂)₀₋₂—(phenyl), C₃-C₆ cycloalkyl, —(CH₂)₀₋₂-(pyridyl),         —(CH₂)₀₋₂—(pyrrolyl), —(CH₂)₀₋₂-(imidazolyl),         —(CH₂)₀₋₂-(pyrimidyl), —(CH₂)₀₋₂-(pyrrolidinyl),         —(CH₂)₀₋₂-(imidazolidinyl), —(CH₂)₀₋₂-(piperazinyl),         —(CH₂)₀₋₂-(piperidinyl), and —(CH₂)₀₋₂-(morpholinyl); wherein         the phenyl group at each occurrence is optionally substituted         with 1 or 2 groups that are independently R₂₀₅ or R₂₁₀; wherein         each heterocycloalkyl group at each occurrence is optionally         substituted with 1 or 2 R₂₁₀; wherein each heteroaryl group at         each occurrence is optionally substituted with 1 or 2 R₂₁₀;     -   R₂₂₀ and R₂₂₅ at each occurrence are independently —H, —C₁-C₄         alkyl, hydroxy C₁-C₄ alkyl, halo C₁-C₄ alkyl; —C₃-C₆ cycloalkyl,         and —(C₁-C₄ alkyl)-O—(C₁-C₂ alkyl);     -   R₂₃₅ and R₂₄₀ at each occurrence are independently H, or C₁-C₆         alkyl;     -   R₂₄₅ and R₂₅₀ at each occurrence are independently H, C₁-C₄         alkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, or     -   R₂₄₅ and R₂₅₀ are taken together with the carbon to which they         are attached to form a carbocycle of 3, 4, 5, or 6 carbon atoms.

Other preferred compounds of formula AA-3 include compounds wherein

-   X is —C₁-C₃ alkylidenyl optionally optionally substituted with 1 or     2 methyl groups; -   Z is SO₂; SO; S; or C(O); -   Y is C₁-C₄ haloalkyl; OH; —N(Y₁) (Y₂); C₁-C₁₀ alkyl optionally     substituted with 1 or 2 substituents which can be the same or     different and are selected from halogen, hydroxy, C₁-C₄ alkoxy,     C₁-C₄ thioalkoxy, and C₁-C₄ haloalkoxy; C₁-C₄ alkoxy; phenyl     optionally substituted with halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CN     or NO₂; and benzyl optionally substituted with halogen, C₁-C₄ alkyl,     C₁-C₄ alkoxy, CN or NO₂; wherein     -   Y₁ and Y₂ are the same or different and are H; C₁-C₆ alkyl         optionally substituted with 1, 2, or 3 substituents selected         from halogen, C₁-C₂ alkoxy, C₃-C₆ cycloalkyl, and OH; C₂-C₆         alkanoyl; phenyl; —SO₂—C₁-C₄ alkyl; benzyl; and C₃-C₆ cycloalkyl         C₁-C₂ alkyl; or     -   —N(Y₁) (Y₂) forms a ring selected from piperazinyl, piperidinyl,         morpholinyl, and pyrolidinyl, wherein each ring is optionally         substituted with 1, 2, 3, or 4 groups that are independently         C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, or halogen.

Preferred compounds of formula AA-3 also include those of formula AA-4, i.e., compounds of formula AA-3 wherein

-   X is —C₁-C₃ alkylidenyl optionally optionally substituted with 1     methyl group; -   Z is SO₂; SO; S; or C(O); -   Y is OH; —N(Y₁)(Y₂); phenyl; benzyl; or C₁-C₁₀ alkyl optionally     substituted with 1 or 2 substituents which can be the same or     different and are selected from halogen, hydroxy, methoxy, ethoxy,     thiomethoxy, thioethoxy, and CF₃; wherein     -   Y₁ and Y₂ are the same or different and are H; C₁-C₄ alkyl         optionally substituted with 1 or 2 substituents selected from         halogen, methoxy, ethoxy, cyclopropyl, and OH; or     -   —N(Y₁) (Y₂) forms a ring selected from piperazinyl, piperidinyl,         morpholinyl, and pyrolidinyl, wherein each ring is optionally         substituted with 1 or 2 groups that are independently C₁-C₄         alkyl, C₁-C₄ alkoxy, or halogen; -   R₁ is benzyl which is optionally substituted with 1, 2, or 3 groups     independently selected from methyl, ethyl, n-propyl, isopropyl,     hydroxymethyl, monohalomethyl, dihalomethyl, trihalomethyl, —CH₂CF₃,     methoxymethyl, halogen, methoxy, ethoxy, n-propyloxy, isopropyloxy,     and OH; -   R₂ and R₃ are independently H or C₁-C₄ alkyl; -   R_(C) is C₁-C₆ alkyl optionally substituted with 1, 2, or 3 R₂₀₅     groups; cyclopropyl, cyclopropylmethyl, cyclopentyl,     cyclopentylmethyl, cyclohexyl, cyclohexylmethyl;     —(CR₂₄₅R₂₅₀)₀₋₃-phenyl optionally substituted with 1 or 2 R₂₀₀     groups; —(CR₂₄₅R₂₅₀)₀₋₃-pyridyl optionally substituted with 1 or 2     R₂₀₀; —(CR₂₄₅R₂₅₀)₀₋₃-piperazinyl; or (CR₂₄₅R₂₅₀)₀₋₃-pyrrolidinyl;     —(CR₂₄₅R₂₅₀)₀₋₃-piperidinyl; each of the above heterocycloalkyl     groups is optionally substituted with 1 or 2 R₂₁₀ groups;     -   R₂₀₀ at each occurrence is independently selected from C₁-C₄         alkyl optionally substituted with 1 or 2 R₂₀₅ groups; OH; and         halogen;     -   R₂₀₅ at each occurrence is independently selected from C₁-C₄         alkyl, halogen, —OH, —SH, —C≡N, —CF₃, and C₁-C₄ alkoxy;     -   R₂₁₀ at each occurrence is independently selected from C₁-C₄         alkyl optionally substituted with 1 or 2 R₂₀₅ groups; halogen;         C₁-C₄ alkoxy; OCF₃; NH₂, NH(C₁-C₆ alkyl); N(C₁-C₆ alkyl) (C₁-C₆         alkyl); OH; and —CO—(C₁-C₄ alkyl); wherein     -   R₂₄₅ and R₂₅₀ at each occurrence are independently selected from         H, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, or     -   R₂₄₅ and R₂₅₀ are taken together with the carbon to which they         are attached to form a carbocycle of 3, 5, or 6 carbon atoms.

Preferred compounds of formulas AA, AA-1 and AA-2 include compounds of formula AA-5, i.e., those of formulae AA, AA-1 or AA-2 wherein

-   one of R_(N) and R_(N)′ is hydrogen and the other is     —C(═O)—(CRR′)₀₋₆R₁₀₀; and -   R₁₀₀ represents aryl, heteroaryl, or heterocyclyl, where the ring     portions of each are optionally substituted with 1, 2, or 3 groups     independently selected from     -   —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,         —(CH₂)₀₋₄—O—P(═O) (OR) (OR′), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,         —(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),         —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),         —(CH₂)₀₋₄—CO—(CH₂)₀₋₄ (C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R₁₁₀,         —(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₄₀,         —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₄₀,         —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅—(CH₂)₀₋₄—SO—(C₁-C₈         alkyl), —(CH₂)₀₋₄—SO₂(C₁-C₁₂ alkyl),         —(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇ cycloalkyl),         —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀, —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂,         —(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅,         —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₋₄—O—CO—(C₁-C₆         alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R₁₀)₂, —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂,         —(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀),         —(CH₂)₀₋₄—O—R₁₅₀′—COOH, —(CH₂)₀₋₄—S—(R₁₅₀),         —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, —(CH₂)₀₋₄—C₃-C₇ cycloalkyl,         (C₂-C₁₀)alkenyl, or (C₂-C₁₀)alkynyl.

Preferred compounds of formula AA-5 include compounds wherein

-   one of R_(N) and R_(N)′ is hydrogen and the other is —C(═O)—R₁₀₀;     and -   R₁₀₀ represents aryl, or heteroaryl, where the ring portions of each     are optionally substituted with 1, 2, or 3 groups independently     selected from     -   —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,         —(CH₂)₀₋₄—O—P(═O) (OR) (OR′), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,         —(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),         —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),         —(CH₂)₀₋₄—CO—(CH₂)₀₋₄(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R₁₁₀,         —(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀,         —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀O₄—CO—R₁₃₀, —(CH₂)₀O₄—CO—R₁₄₀,         —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅,         —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂ (C₁-C₁₂ alkyl),         —(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇ cycloalkyl),         —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀, —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂,         —(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅,         —(CH₂)₀₋₄—NR₁₀₅R′₁₅₀, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₋₄—O—CO—(C₁-C₆         alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂, —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂,         —(CH₂)₀O₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀),         —(CH₂)₀₋₄—O—R₁₅₀—COOH, —(CH₂)₀₋₄—S—(R₁₅₀),         —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, —(CH₂)₀₋₄—C₃-C₇ cycloalkyl,         (C₂-C₁₀)alkenyl, or (C₂-C₁₀) alkynyl.

Preferred compounds of formula AA-5 also include compounds wherein

-   one of R_(N) and R_(N)′ is hydrogen and the other is —C(═O)-aryl or     —C(═O)-heteroaryl where the ring portions of each are optionally     substituted with 1, 2, or 3 groups independently selected from     -   —OR, —NO₂, C₁-C₆ alkyl, halogen, —CO≡N, —OCF₃, —CF₃,         —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′,         —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl),         —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl), —(CH₂)₀₋₄—R₁₁₀—(CH₂)₀₋₄—R₁₂₀,         —(CH₂)₀₋₄—R₁₃₀—(CH₂)₀₋₄—CO—R₁₁₀,         —(CH₂)₀₋₄—CO—R₁₂₀—(CH₂)₀₋₄—CO—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₄₀,         —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅—(CH₂)₀₋₄—SO—(C₁-C₈         alkyl), —(CH₂)₀₋₄—SO₂ (C₁-C₁₂ alkyl),         —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀, —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂,         —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅, —(CH₂)₀₋₄—NR₁₀₅R′₁₅₀—(CH₂)₀₋₄—R₁₄₀,         —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl), —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂,         —(CH₂)₀₋₄—O—(R₁₅₀), —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, —(CH₂)₀₋₄—C₃-C₇         cycloalkyl, (C₂-C₁₀) alkenyl, or (C₂-C₁₀) alkynyl.

Other preferred compounds of formula AA-5 include compounds wherein

-   one of R_(N) and R_(N)′ is hydrogen and the other is —C(═O)-aryl or     —C(═O)-heteroaryl where the ring portions of each are optionally     substituted with 1 or 2 groups independently selected from     -   C₁-C₆ alkyl, halogen, —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,         —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅,         —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅, C₃-C₇ cycloalkyl, (C₂-C₁₀) alkenyl,         —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀, or (C₂-C₁₀)         alkynyl.

Other preferred compounds of formula AA-5 include compounds wherein

-   one of R_(N) and R_(N)′ is hydrogen and the other is —C(═O)-phenyl,     where the phenyl ring is optionally substituted with 1 or 2 groups     independently selected from     -   C₁-C₆ alkyl, halogen, —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅, —(CH₂)_(0-—)         ₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅,         —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅, C₃-C₇ cycloalkyl, (C₂-C₁₀) alkenyl,         —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀—(CH₂)₀₋₄—R₁₃₀, or (C₂-C₁₀)         alkynyl.

Other preferred compounds of formula AA-5 also include compounds wherein one of R_(N) and R_(N)′ is hydrogen and the other is:

-   -   wherein sub is hydrogen or is C₁-C₆ alkyl, halogen,         —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂,         —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅, C₃-C₇         cycloalkyl, —(C₂-C₁₀) alkenyl, —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀,         —(CH₂)₀₋₄—R₁₃₀, or (C₂-C₁₀) alkynyl.

A preferred stereochemistry for compounds of formula AA is as follows:

Preferred compounds of formula I include those of formula I-1, i.e., compounds of formula I wherein

-   R₁ is aryl, heteroaryl, heterocyclyl, —C₁-C₆ alkyl-aryl, —C₁-C₆     alkyl-heteroaryl, or —C₁-C₆ alkyl-heterocyclyl, where the ring     portions of each are optionally substituted with 1, 2, 3, or 4     groups independently selected from halogen, —OH, —SH, —C≡N, —NO₂,     —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′, or —N(R)SO₂R′, —C(═O)—(C₁-C₄) alkyl,     —SO₂-amino, —SO₂-mono or dialkylamino, —C(═O)-amino, —C(═O)-mono or     dialkylamino, —SO₂—(C₁-C₄) alkyl, or     -   C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups which         are independently selected from halogen, or     -   C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃         alkoxy, amino, —C₁-C₆ alkyl and mono- or dialkylamino, or     -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, —OH, —SH, —C≡N, —CF₃,         —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, or     -   C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally         substituted with 1, 2, or 3 groups independently selected from         halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl         and mono- or dialkylamino; and the heterocyclyl group is         optionally further substituted with oxo.

Preferred compounds of formula I-1 also include those wherein

-   R₁ is —C₁-C₆ alkyl-aryl, —C₁-C₆ alkyl-heteroaryl, or —C₁-C₆     alkyl-heterocyclyl, where the ring portions of each are optionally     substituted with 1, 2, 3, or 4 groups independently selected from     halogen, —OH, —SH, —C≡N, —NO₂, —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′, or     —N(R)SO₂R′, —C(═O)—(C₁-C₄) alkyl, —SO₂-amino, —SO₂-mono or     dialkylamino, —C(═O)-amino, —C(═O)-mono or dialkylamino,     —SO₂—(C₁-C₄) alkyl, or     -   C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups which         are independently selected from halogen, or     -   C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃         alkoxy, amino, —C₁-C₆ alkyl and mono- or dialkylamino, or     -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, —OH, —SH, —C≡N, —CF₃,         —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, or     -   C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally         substituted with 1, 2, or 3 groups independently selected from         halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl         and mono- or dialkylamino; and the heterocyclyl group is         optionally further substituted with oxo.

Preferred compounds of formula I-1 further include those wherein

-   R₁ is —(CH₂)-aryl, —(CH₂)-heteroaryl, or —(CH₂)-heterocyclyl, where     the ring portions of each are optionally substituted with 1, 2, 3,     or 4 groups independently selected from halogen, —OH, —SH, —C≡N,     —NO₂, —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′, or —N(R)SO₂R, —C(═O)—(C₁-C₄)     alkyl, —SO₂-amino, —SO₂-mono or dialkylamino, —C(═O)-amino,     —C(═O)-mono or dialkylamino, —SO₂—(C₁-C₄) alkyl, or     -   C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups which         are independently selected from halogen, or     -   C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃         alkoxy, amino, —C₁-C₆ alkyl and mono- or dialkylamino, or     -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, —OH, —SH, —C≡N, —CF₃,         —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, or     -   C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally         substituted with 1, 2, or 3 groups independently selected from         halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl         and mono- or dialkylamino; and the heterocyclyl group is         optionally further substituted with oxo.

Preferred compounds of formula I-1 also include those wherein

-   R₁ is —CH₂-phenyl or —CH₂-pyridinyl where the ring portions of each     are optionally substituted with 1, 2, 3, or 4 groups independently     selected from halogen, C₁-C₄ alkoxy, hydroxy, —NO₂, and     -   C₁-C₄ alkyl optionally substituted with 1, 2, or 3 substituents         independently selected from halogen, OH, SH, NH₂, NH(C₁-C₆         alkyl), N—(C₁-C₆ alkyl)(C₁-C₆ alkyl), C≡N, CF₃.

Preferred compounds of formula I-1 further include those wherein

-   R₁ is —CH₂-phenyl or —CH₂-pyridinyl where the phenyl or pyridinyl     rings are each optionally substituted with 1 or 2 groups     independently selected from halogen, C₁-C₂ alkyl, C₁-C₂ alkoxy,     hydroxy, —CF₃, and —NO₂.

Preferred compounds of formula I-1 include those wherein

-   R₁ is —CH₂-phenyl where the phenyl ring is optionally substituted     with 2 groups independently selected from halogen, C₁-C₂ alkyl,     C₁-C₂ alkoxy, hydroxy, and —NO₂.

Preferred compounds of formula I-1 also include those wherein R₁ is benzyl, or 3,5-difluorobenzyl.

Preferred compounds of formula I and I-1 include those of formula I-2, i.e., compounds of formula I or I-1 wherein

-   R₂ and R₃ are independently selected from H or C₁-C₆ alkyl     optionally substituted with 1, 2, or 3 substituents selected from     the group consisting of C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃,     C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b).

Preferred compounds of formula I-2 include those wherein

-   R_(C) is selected from the group consisting of C₁-C₁₀ alkyl     optionally substituted with 1, 2, or 3 groups independently selected     from the group consisting of R₂₀₅, —OC═ONR₂₃₅R₂₄₀, —S(═O)₀₋₂ (C₁-C₆     alkyl), —SH, —NR₂₃₅C═ONR₂₃₅R₂₄₀, —C═ONR₂₃₅R₂₄₀, and     —S(═O)₂NR₂₃₅R₂₄₀; —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl wherein the     cycloalkyl is optionally substituted with 1, 2, or 3 groups     independently selected from the group consisting of R₂₀₅, —CO₂H, and     —CO₂—(C₁-C₄ alkyl); —(CR₂₄₅R₂₅₀)₀₋₄-aryl;     —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl; —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl;     —[C(R₂₅₅) (R₂₆₀)]₁₋₃—CO—N—(R₂₅₅)₂; —CH(aryl)₂; —CH(heteroaryl)₂;     —CH(heterocycloalkyl)₂; —CH(aryl) (heteroaryl); —CO—NR₂₃₅R₂₄₀;     —(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH)—(CH₂) O₁-aryl;     —(CH₂)₀₋₁—CHR_(C-6)—(CH₂)₀₋₁-heteroaryl; —CH(-aryl or     -heteroaryl)-CO—O(C₁-C₄ alkyl); —CH(—CH₂—OH)—CH(OH)-phenyl-NO₂;     (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-OH; —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂; —H;     and —(CH₂)₀₋₆—C(═NR₂₃₅) (NR₂₃₅R₂₄₀); wherein     -   each aryl is optionally substituted with 1, 2, or 3 R₂₀₀;     -   each heteroaryl is optionally substituted with 1, 2, 3, or 4         R₂₀₀;     -   each heterocycloalkyl is optionally substituted with 1, 2, 3, or         4 R₂₁₀;     -   R₂₀₀ at each occurrence is independently selected from the group         consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3         R₂₀₅ groups; OH; —NO₂; halogen; —CO₂H; CON;         —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl);         —(CH₂)₀₋₄—CO₂R₂₁₅; and —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally         substituted with 1, 2, 3, or 5-F);         -   wherein each aryl group at each occurrence is optionally             substituted with 1, 2, or 3 groups that are independently             R₂₀₅, R₂₁₀ or C₁-C₆ alkyl substituted with 1, 2, or 3 groups             that are independently R₂₀₅ or R₂₁₀;         -   wherein each heterocycloalkyl group at each occurrence is             optionally substituted with 1, 2, or 3 groups that are             independently R₂₁₀;         -   wherein each heteroaryl group at each occurrence is             optionally substituted with 1, 2, or 3 groups that are             independently R₂₀₅, R₂₁₀, or C₁-C₆ alkyl substituted with 1,             2, or 3 groups that are independently R₂₀₅ or R₂₁₀;     -   R₂₀₅ at each occurrence is independently selected from the group         consisting of C₁-C₆ alkyl, halogen, —OH, —O-phenyl, —SH, —C≡N,         —CF₃, C₁-C₆ alkoxy, NH₂, NH(C₁-C₆ alkyl), and N-(C₁-C₆ alkyl)         (C₁-C₆ alkyl);     -   R₂₁₀ at each occurrence is independently selected from the group         consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3         R₂₀₅ groups; halogen; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy;         —NR₂₂₀R₂₂₅; OH; C≡N; C₃-C₇ cycloalkyl optionally substituted         with 1, 2, or 3 R₂₀₅ groups; —CO—(C₁-C₄ alkyl); SO₂NR₂₃₅R₂₄₀;         —CO—NR₂₃₅R₂₄₀; —SO₂—(C₁-C₄ alkyl); and ═O; wherein     -   R₂₁₅ at each occurrence is independently selected from the group         consisting of C₁-C₆ alkyl, —(CH₂)₀₋₂—(aryl), C₃-C₇ cycloalkyl,         and —(CH₂)₀₋₂-(heteroaryl), —(CH₂)₀₋₂-(heterocycloalkyl);         wherein the aryl group at each occurrence is optionally         substituted with 1, 2, or 3 groups that are independently R₂₀₅         or R₂₁₀; wherein the heterocycloalkyl group at each occurrence         is optionally substituted with 1, 2, or 3 R₂₁₀; wherein each         heteroaryl group at each occurrence is optionally substituted         with 1, 2, or 3 R₂₁₀;     -   R₂₂₀ and R₂₂₅ at each occurrence are independently selected from         the group consisting of —H, —C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl,         amino C₁-C₆ alkyl; halo C₁-C₆ alkyl; —C₃-C₇ cycloalkyl, —(C₁-C₆         alkyl)-O—(C₁-C₃ alkyl), -aryl, -heteroaryl, and         -heterocycloalkyl; wherein the aryl group at each occurrence is         optionally substituted with 1, 2, or 3 R₂₇₀ groups, each         heteroaryl is optionally substituted with 1, 2, 3, or 4 R₂₀₀,         each heterocycloalkyl is optionally substituted with 1, 2, 3, or         4 R₂₁₀ wherein     -   R₂₇₀ at each occurrence is independently R₂₀₅, C₁-C₆ alkyl         optionally substituted with 1, 2, or 3 R₂₀₅ groups; halogen;         C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; NR₂₃₅R₂₄₀; OH; C≡N; —CO—(C₁-C₄         alkyl); and ═O; wherein the heterocycloalkyl group at each         occurrence is optionally substituted with 1, 2, or 3 R₂₀₅         groups; wherein each heteroaryl group at each occurrence is         optionally substituted with 1, 2, or 3 R₂₀₅ groups;     -   R₂₃₅ and R₂₄₀ at each occurrence are independently H, or C₁-C₆         alkyl;     -   R₂₄₅ and R₂₅₀ at each occurrence are independently selected from         the group consisting of H, C₁-C₄ alkyl, C₁-C₄ hydroxyalkyl,         C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, or     -   R₂₄₅ and R₂₅₀ are taken together with the carbon to which they         are attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon         atoms, wherein the carbocycle is optionally substituted with 1         or 2 groups that are independently OH, methyl, Cl, F, OCH₃, CF₃,         NO₂, or CN;     -   R₂₅₅ and R₂₆₀ at each occurrence are independently selected from         the group consisting of H; C₁-C₆ alkyl optionally substituted         with 1, 2, or 3 R₂₀₅ groups; —(CH₂)₀₋₄—C₃-C₇ cycloalkyl         optionally substituted with 1, 2, or 3 R₂₀₅ groups; —(C₁-C₄         alkyl)-aryl; —(C₁-C₄ alkyl)-heteroaryl; —(C₁-C₄         alkyl)-heterocycloalkyl; aryl; heteroaryl; heterocycloalkyl;         —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-aryl;         —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heteroaryl; and;         —(CH₂)₁₋₄—R₂₆₅—(CH₂)_(0-—) ₄-heterocycloalkyl; wherein         -   R₂₆₅ at each occurrence is independently —O—, —S— or             —N(C₁-C₆ alkyl)-;         -   each aryl or phenyl is optionally substituted with 1, 2, or             3 groups that are independently R₂₀₅, R₂₁₀, or C₁-C₆ alkyl             substituted with 1, 2, or 3 groups that are independently             R₂₀₅ or R₂₁₀.

Preferred compounds of formula I-2 include those wherein:

-   R_(C) is —(CR₂₄₅R₂₅₀)₀₋₄-aryl, or —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl,     wherein aryl and heteroaryl are optionally substituted with 1, 2, or     3 R₂₀₀ groups.

Preferred compounds of formula I-2 also include compounds wherein

-   R_(C) is —(CR₂₄₅R₂₅₀)-aryl, or —(CR₂₄₅R₂₅₀)-heteroaryl wherein each     aryl and heteroaryl is optionally substituted with 1, 2, or 3 R₂₀₀     groups.

Preferred compounds of formula I-2 also include compounds wherein

-   -   R_(C) is —(CH₂)-aryl, or —(CH₂)-heteroaryl, wherein     -   each aryl and heteroaryl is optionally substituted with 1, 2, or         3 groups selected from OH, —NO₂, halogen, —CO₂H, C—N,         —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), and         —(CH₂)₀₋₄—SO₂—NR₂₂₀R₂₂₅.

Preferred compounds of formula I-2 also include compounds wherein

-   R_(C) is —(CH₂)-aryl, wherein aryl is optionally substituted with 1,     2, or 3 groups selected from OH, —NO₂, halogen, —CO₂H, and C≡N.

Preferred compounds of formula I-2 also include compounds wherein

-   R_(C) is —(CH₂)-phenyl, wherein phenyl is optionally substituted     with 1, 2, or 3 groups selected from OH, —NO₂, halogen, —CO₂H, and     C≡N.

Preferred compounds of formula I-2 also include compounds wherein R_(C) is benzyl.

Other preferred compounds of formulas I, I-1 and I-2 include compounds of formula I-3, i.e., those of formulas I, I-1 or I-2 wherein

-   -   R_(N) is:

-   -   wherein

-   R₄ is NH₂; —NH—(CH₂)_(n6)—R₄₋₁; —NHR₈; —NR₅₀C(O)R₅; or —NR₅₀CO₂R₅₁;     -   wherein         -   n₆ is 0, 1, 2, or 3;         -   n₇ is 0, 1, 2, or 3;     -   R₄₋₁ is selected from the group consisting of —SO₂—(C₁-C₈         alkyl), —SO—(C₁-C₈ alkyl), —S—(C₁-C₈ alkyl), —S—CO—(C₁-C₆         alkyl), —SO₂—NR₄₋₂R₄₋₃; —CO—C₁-C₂ alkyl; —CO—NR₄₋₃R₄₋₄;     -   R₄₋₂ and R₄₋₃ are independently H, C₁-C₃ alkyl, or C₃-C₆         cycloalkyl;     -   R₄₋₄ is alkyl, phenylalkyl, C₂-C₄ alkanoyl, or phenylalkanoyl;

-   R₅ is cyclopropyl; cyclobutyl; cyclopentyl; and cyclohexyl; wherein     each cycloalkyl group is optionally substituted with one or two     groups that are C₁-C₆ alkyl, more preferably C₁-C₂ alkyl, C₁-C₆     alkoxy, more preferably C₁-C₂ alkoxy, CF₃, OH, NH₂, NH(C₁-C₆ alkyl),     N(C₁-C₆ alkyl) (C₁-C₆ alkyl), halogen, CN, or NO₂; or the cycloalkyl     group is substituted with 1 or 2 groups that are independently CF₃,     Cl, F, methyl, ethyl or cyano; C₁-C₆ alkyl optionally substituted     with 1, 2, or 3 groups that are independently halogen, —NR₆R₇, C₁-C₄     alkoxy, C₅-C₆ heterocycloalkyl, C₅-C₆ heteroaryl, phenyl, C₃-C₇     cycloalkyl, —S—C₁-C₄ alkyl, —SO₂—C₁-C₄ alkyl, —CO₂H, —CONR₆R₇,     —CO₂—C₁-C₄ alkyl, or phenyloxy; heteroaryl optionally substituted     with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄     alkoxy, halogen, C₁-C₄ haloalkyl, or OH; heterocycloalkyl optionally     substituted with 1, 2, or 3 groups that are independently C₁-C₄     alkyl, C₁-C₄ alkoxy, halogen, or C₂-C₄ alkanoyl; phenyl optionally     substituted with 1, 2, 3, or 4 groups that are independently     halogen, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₁-C₄ haloalkyl; and     —NR₆R₇; wherein     -   R₆ and R₇ are independently selected from the group consisting         of H, C₁-C₆ alkyl, C₂-C₆ alkanoyl, phenyl, —SO₂—C₁-C₄ alkyl, and         phenyl C₁-C₄ alkyl;     -   R₈ is selected from the group consisting of —SO₂-heteroaryl         optionally substituted with 1 or 2 groups that are independently         C₁-C₄ alkyl or halogen;, —SO₂-aryl, —SO₂-heterocycloalkyl,         —C(O)NHR₉, heterocycloalkyl, —S—C₂-C₄ alkanoyl, wherein         -   R₉ is phenyl C₁-C₄ alkyl, C₁-C₆ alkyl, or H; R₅₀ is H or             C₁-C₆ alkyl;     -   R₅₁ is selected from the group consisting of phenyl C₁-C₄ alkyl;         C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that         are independently halogen, cyano, —NR₆R₇, —C(O)NR₆R₇, C₃-C₇ or         —C₁-C₄ alkoxy; heterocycloalkyl optionally substituted with 1 or         2 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, C₂-C₄ alkanoyl, phenyl C₁-C₄ alkyl, and —SO₂ C₁-C₄         alkyl; heterocycloalkylalkyl optionally substituted with 1 or 2         groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, C₂-C₄ alkanoyl, phenyl C₁-C₄ alkyl, and —SO₂ C₁-C₄         alkyl; alkenyl; alkynyl; heteroaryl optionally substituted with         1, 2, or 3 groups that are independently OH, C₁-C₄ alkyl, C₁-C₄         alkoxy, halogen, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆         alkyl); heteroarylalkyl optionally substituted with 1, 2, or 3         groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl);         phenyl; C₃-C₈ cycloalkyl, and cycloalkylalkyl, wherein the         phenyl; C₃-C₈ cycloalkyl, and cycloalkylalkyl groups are         optionally substituted with 1, 2, 3, 4 or 5 groups that are         independently halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆         alkanoyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, hydroxy, C₁-C₆         hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ thioalkoxy, C₁-C₆         thioalkoxy C₁-C₆ alkyl, or C₁-C₆ alkoxy C₁-C₆ alkoxy.

Preferred compounds of formula I-3 include compounds wherein

-   -   R_(N) is

-   -   wherein

-   X is C₁-C₄ alkylidenyl optionally substituted with 1, 2, or 3 methyl     groups; or —NR₄₋₆—; or     -   R₄ and R₄₋₆ combine to form —(CH₂)_(n10)—, wherein n₁₀ is 1, 2,         3, or 4;

-   Z is selected from a bond; SO₂; SO; S; and C(O);

-   Y is selected from H; C₁-C₄ haloalkyl; C₅-C₆ heterocycloalkyl     containing at least one N, O, or S; phenyl; OH; —N(Y₁) (Y₂); C₁-C₁₀     alkyl optionally substituted with 1 thru 3 substituents which can be     the same or different and are selected from halogen, hydroxy,     alkoxy, thioalkoxy, and haloalkoxy; C₃-C₈ cycloalkyl optionally     substituted with 1, 2, or 3 groups independently selected from C₁-C₃     alkyl, and halogen; alkoxy; phenyl optionally substituted with     halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CN or NO₂; phenyl C₁-C₄ alkyl     optionally substituted with halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CN     or NO₂; wherein     -   Y₁ and Y₂ are the same or different and are H; C₁-C₁₀ alkyl         optionally substituted with 1, 2, or 3 substituents selected         from the group consisting of halogen, C₁-C₄ alkoxy, C₃-C₈         cycloalkyl, and OH; C₂-C₆ alkenyl; C₂-C₆ alkanoyl; phenyl;         —SO₂—C₁-C₄ alkyl; phenyl C₁-C₄ alkyl; and C₃-C₈ cycloalkyl C₁-C₄         alkyl; or     -   —N(Y₁) (Y₂) forms a ring selected from piperazinyl, piperidinyl,         morpholinyl, and pyrolidinyl, wherein each ring is optionally         substituted with 1, 2, 3, or 4 groups that are independently         C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, or halogen.

Preferred compounds of formula I-3 include compounds wherein

-   X is C₁-C₄ alkylidenyl optionally optionally substituted with 1, 2,     or 3 methyl groups; -   Z is selected from SO₂; SO; S; and C(O); -   Y is selected from H; C₁-C₄ haloalkyl; C₅-C₆ heterocycloalkyl     containing at least one N, O, or S; phenyl; OH; —N(Y₁) (Y₂); C₁-C₁₀     alkyl optionally substituted with 1 thru 3 substituents which can be     the same or different and are selected from the group consisting of     halogen, hydroxy, alkoxy, thioalkoxy, and haloalkoxy; C₃-C₈     cycloalkyl optionally substituted with 1, 2, or 3 groups     independently selected from C₁-C₃ alkyl, and halogen; alkoxy; phenyl     optionally substituted with halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CN     or NO₂; phenyl C₁-C₄ alkyl optionally substituted with halogen,     C₁-C₄ alkyl, C₁-C₄ alkoxy, CN or NO₂; wherein     -   Y₁ and Y2 are the same or different and are H; C₁-C₆ alkyl         optionally substituted with 1, 2, or 3 substituents selected         from the group consisting of halogen, C₁-C₄ alkoxy, C₃-C₈         cycloalkyl, and OH; C₂-C₆ alkenyl; C₂-C₆ alkanoyl; phenyl;         —SO₂—C₁-C₄ alkyl; phenyl C₁-C₄ alkyl; or C₃-C₈ cycloalkyl C₁-C₄         alkyl; or     -   —N(Y₁) (Y₂) forms a ring selected from piperazinyl, piperidinyl,         morpholinyl, and pyrolidinyl, wherein each ring is optionally         substituted with 1, 2, 3, or 4 groups that are independently         C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, or halogen.

Preferred compounds of formula I-3 include compounds wherein R_(N) is

-   -   and wherein R₄ is NH₂; —NH—(CH₂)_(n6)—R₄₋₁; —NHR₈; —NR₅₀C(O)R₅;         or —NR₅₀CO₂R₅₁ wherein         -   n₆ is 0, 1, 2, or 3;         -   n₇ is 0, 1, 2, or 3;     -   R₄₋₁ is selected from the group consisting of —SO₂—(C₁-C₈         alkyl), —SO—(C₁-C₈ alkyl), —S—(C₁-C₈ alkyl), —S—CO—(C₁-C₆         alkyl), —SO₂—NR₄₋₂R₄₋₃; —CO—C₁-C₂ alkyl; —CO—NR₄₋₃R₄₋₄;     -   R₄₋₂ and R₄₋₃ are independently H, C₁-C₃ alkyl, or C₃-C₆         cycloalkyl;     -   R₄₋₄ is alkyl, phenylalkyl, C₂-C₄ alkanoyl, or phenylalkanoyl;     -   R₅ is cyclopropyl; cyclobutyl; cyclopentyl; or cyclohexyl;         wherein each cycloalkyl group is optionally substituted with one         or two groups that are C₁-C₆ alkyl, more preferably C₁-C₂ alkyl,         C₁-C₆ alkoxy, more preferably C₁-C₂ alkoxy, CF₃, OH, NH₂,         NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl) (C₁-C₆ alkyl), halogen, CN, or         NO₂; or the cycloalkyl group is substituted with 1 or 2 groups         that are independently CF₃, Cl, F, methyl, ethyl or cyano; C₁-C₆         alkyl optionally substituted with 1, 2, or 3 groups that are         independently halogen, —NR₆R₇, C₁-C₄ alkoxy, C₅-C₆         heterocycloalkyl, C₅-C₆ heteroaryl, phenyl, C₃-C₇ cycloalkyl,         —S—C₁-C₄ alkyl, —SO₂—C₁-C₄ alkyl, —CO₂H, —CONR₆R₇, —CO₂—C₁-C₄         alkyl, or phenyloxy; heteroaryl optionally substituted with 1,         2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, C₁-C₄ haloalkyl, or OH; heterocycloalkyl optionally         substituted with 1, 2, or 3 groups that are independently C₁-C₄         alkyl, C₁-C₄ alkoxy, halogen, or C₂-C₄ alkanoyl; phenyl         optionally substituted with 1, 2, 3, or 4 groups that are         independently halogen, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₁-C₄         haloalkyl; and —NR₆R₇; wherein     -   R₆ and R₇ are independently selected from the group consisting         of H, C₁-C₆ alkyl, C₂-C₆ alkanoyl, phenyl, —SO₂—C₁-C₄ alkyl, and         phenyl C₁-C₄ alkyl;     -   R₈ is selected from the group consisting of —SO₂-heteroaryl         optionally substituted with 1 or 2 groups that are independently         C₁-C₄ alkyl or halogen;, —SO₂-aryl, —SO₂-heterocycloalkyl,         —C(O)NHR₉, heterocycloalkyl, —S—C₂-C₄ alkanoyl, wherein         -   R₉ is phenyl C₁-C₄ alkyl, C₁-C₆ alkyl, or H; R₅₀ is H or             C₁-C₆ alkyl; and     -   R₅₁ is selected from the group consisting of phenyl C₁-C₄ alkyl;         C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that         are independently halogen, cyano, —NR₆R₇, —C(O)NR₆R₇, C₃-C₇ or         —C₁-C₄ alkoxy; heterocycloalkyl optionally substituted with 1 or         2 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, C₂-C₄ alkanoyl, phenyl C₁-C₄ alkyl, and —SO₂ C₁-C₄         alkyl; heterocycloalkylalkyl optionally substituted with 1 or 2         groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, C₂-C₄ alkanoyl, phenyl C₁-C₄ alkyl, and —SO₂ C₁-C₄         alkyl; alkenyl; alkynyl; heteroaryl optionally substituted with         1, 2, or 3 groups that are independently OH, C₁-C₄ alkyl, C₁-C₄         alkoxy, halogen, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆         alkyl); heteroarylalkyl optionally substituted with 1, 2, or 3         groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl);         phenyl; C₃-C₈ cycloalkyl, and cycloalkylalkyl, wherein the         phenyl; C₃-C₈ cycloalkyl, and cycloalkylalkyl groups are         optionally substituted with 1, 2, 3, 4 or 5 groups that are         independently halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆         alkanoyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, hydroxy, C₁-C₆         hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ thioalkoxy, C₁-C₆         thioalkoxy C₁-C₆ alkyl, or C₁-C₆ alkoxy C₁-C₆ alkoxy; and

-   Y is C₁-C₁₀ alkyl optionally substituted with 1 thru 3 substituents     which can be the same or different and are selected from halogen,     hydroxy, alkoxy, thioalkoxy, and haloalkoxy.

Preferred compounds of formula I-3 further include compounds wherein

-   R_(C) is C₁-C₈ alkyl optionally substituted with 1, 2, or 3 groups     independently selected from the group consisting of R₂₀₅,     —OC═ONR₂₃₅R₂₄₀, —S(═O)₀₋₂ (C₁-C₆ alkyl), —SH, —C═ONR₂₃₅R₂₄₀, and     —S(═O)₂NR₂₃₅R₂₄₀; —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl wherein the     cycloalkyl is optionally substituted with 1, 2, or 3 groups     independently selected from the group consisting of R₂₀₅-CO₂H, and     —CO₂—(C₁-C₄ alkyl); —(CR₂₄₅R₂₅₀)₀₋₄-phenyl;     —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl; —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl;     —(CH₂)₀₋₁—CH((CH₂)₀₋₄—OH)—(CH₂)₀₋₁-phenyl;     —(CH₂)₀₋₁—CHR_(C-6)—(CH₂)₀₋₁-heteroaryl;     —CH(—CH₂—OH)—CH(OH)-phenyl-NO₂; (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-OH; or     —(CH₂)₀₋₆—C(═NR₂₃₅)(NR₂₃₅R₂₄₀); wherein     -   each aryl is optionally substituted with 1, 2, or 3 R₂₀₀;     -   each heteroaryl is optionally substituted with 1, 2, 3, or 4         R₂₀₀;     -   each heterocycloalkyl is optionally substituted with 1, 2, 3, or         4 R₂₁₀;     -   R₂₀₀ at each occurrence is independently C₁-C₆ alkyl optionally         substituted with 1, 2, or 3 R₂₀₅ groups; OH; —NO₂; halogen;         —CO₂H; C≡N; —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl);         —(CH₂)₀₋₄—CO₂R₂₁₅; or —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally         substituted with 1, 2, 3, or 5-F);     -   R₂₀₅ at each occurrence is independently C₁-C₆ alkyl, halogen,         —OH, —O-phenyl, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, NH₂, NH(C₁-C₆         alkyl), or N—(C₁-C₆ alkyl) (C₁-C₆ alkyl);     -   R₂₁₀ at each occurrence is independently C₁-C₆ alkyl optionally         substituted with 1, 2, or 3 R₂₀₅ groups; halogen; C₁-C₆ alkoxy;         C₁-C₆ haloalkoxy; —NR₂₂₀R₂₂₅; OH; C≡N; C₃-C₇ cycloalkyl         optionally substituted with 1, 2, or 3 R₂₀₅ groups; —CO—(C₁-C₄         alkyl); SO₂NR₂₃₅R₂₄₀; —CO—NR₂₃₅R₂₄₀; —SO₂—(C₁-C₄ alkyl); and ═O;         wherein     -   R₂₁₅ at each occurrence is independently C₁-C₆ alkyl,         —(CH₂)₀₋₂-(phenyl), C₃-C₇ cycloalkyl, and         —(CH₂)₀₋₂-(heteroaryl), —(CH₂)₀₋₂-(heterocycloalkyl); wherein         the phenyl group at each occurrence is optionally substituted         with 1, 2, or 3 groups that are independently R₂₀₅ or R₂₁₀;         wherein the heterocycloalkyl group at each occurrence is         optionally substituted with 1, 2, or 3 R₂₁₀; wherein each         heteroaryl group at each occurrence is optionally substituted         with 1, 2, or 3 R₂₁₀;     -   R₂₂₀ and R₂₂₅ at each occurrence are independently —H, —C₁-C₆         alkyl, hydroxy C₁-C₆ alkyl, halo C₁-C₆ alkyl; —C₃-C₇ cycloalkyl,         and —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl);     -   R₂₃₅ and R₂₄₀ at each occurrence are independently H, or C₁-C₆         alkyl;     -   R₂₄₅ and R₂₅₀ at each occurrence are independently H, C₁-C₄         alkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, or     -   R₂₄₅ and R₂₅₀ are taken together with the carbon to which they         are attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon         atoms.

Preferred compounds of formula I-3 include compounds wherein

-   R₁ is benzyl which is optionally substituted with 1, 2, 3, or 4     groups independently selected from halogen, C₁-C₄ alkoxy, hydroxy,     and C₁-C₄ alkyl optionally substituted with 1, 2, or 3 substituents     halogen, OH, SH, NH₂, NH(C₁-C₆ alkyl), N—(C₁-C₆ alkyl)(C₁-C₆ alkyl),     C—N, CF₃; -   R₂ and R₃ are independently selected from H or C₁-C₄ alkyl     optionally substituted with 1 substituent selected from halogen,     —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, NH₂, NH(C₁-C₆ alkyl), and     NH(C₁-C₆ alkyl) (C₁-C₆ alkyl); -   R_(C) is C₁-C₈ alkyl optionally substituted with 1, 2, or 3 groups     independently selected from R₂₀₅, —SH, —C═ONR₂₃₅R₂₄₀, and     —S(═O)₂NR₂₃₅R₂₄₀; —(CH₂)₀₋₃ (C₃-C₆) cycloalkyl wherein the     cycloalkyl is optionally substituted with 1, 2, or 3 groups     independently selected from R₂₀₅, —CO₂H, and —CO₂—(C₁-C₄ alkyl);     —(CR₂₄₅R₂₅₀)₀₋₄-phenyl optionally substituted with 1, 2, or 3 R₂₀₀;     —(CR₂₄₅R₂₅₀)₀₋₃-pyridyl; —(CR₂₄₅R₂₅₀)₀₋₃-pyridazinyl;     —(CR₂₄₅R₂₅₀)₀₋₃-pyrimidinyl; —(CR₂₄₅R₂₅₀)₀₋₃-pyrazinyl;     —(CR₂₄₅R₂₅₀)₀₋₃-furyl; —(CR₂₄₅R₂₅₀)₀₋₃-indolyl;     —(CR₂₄₅R₂₅₀)₀₋₃-thienyl; —(CR₂₄₅R₂₅₀)₀₋₃-pyrrolyl;     —(CR₂₄₅R₂₅₀)₀₋₃-pyrazolyl; (CR₂₄₅R₂₅₀)₀₋₃-benzoxazolyl;     —(CR₂₄₅R₂₅₀)₀₋₃-imidazolyl; each of the above heteroaryl groups is     optionally substituted with 1, 2, 3, or 4 R₂₀₀;     —(CR₂₄₅R₂₅₀)₀₋₃-imidazolidinyl; (CR₂₄₅R₂₅₀)₀₋₃-tetrahydrofuryl;     (CR₂₄₅R₂₅₀)₀₋₃-tetrahydropyranyl; (CR₂₄₅R₂₅₀)₀₋₃-piperazinyl;     (CR₂₄₅R₂₅₀)₀₋₃-pyrrolidinyl; (CR₂₄₅R₂₅₀)₀₋₃-piperidinyl;     (CR₂₄₅R₂₅₀)₀₋₃-indolinyl; each of the above heterocycloalkyl groups     is optionally substituted with 1, 2, 3, or 4 R₂₁₀;     (CH₂)₀₋₁—CH((CH₂)₀₋₄—OH)—(CH₂)₀₋₁-phenyl; —(CH₂)₀₋₁—CH(C₁-C₄     hydroxyalkyl)-(CH₂)₀₋₁ pyridyl;     -   R₂₀₀ at each occurrence is independently C₁-C₆ alkyl optionally         substituted with 1, 2, or 3 R₂₀₅ groups; OH; —NO₂; halogen;         —CO₂H; C≡N; —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—CO—(C₁-C₈ alkyl);         —(CH₂)₀₋₄—CO₂R₂₁₅; and —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally         substituted with 1, 2, 3, or 5-F);     -   R₂₀₅ at each occurrence is independently C₁-C₆ alkyl, halogen,         —OH, —O-phenyl, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, NH₂, NH(C₁-C₆         alkyl), and N—(C₁-C₆ alkyl) (C₁-C₆ alkyl);     -   R₂₁₀ at each occurrence is independently C₁-C₆ alkyl optionally         substituted with 1 or 2 R₂₀₅ groups; halogen; C₁-C₄ alkoxy;         C₁-C₄ haloalkoxy; —NR₂₂₀R₂₂₅; OH; CN; C₃-C₇ cycloalkyl         optionally substituted with 1 or 2 R₂₀₅ groups; —CO—(C₁-C₄         alkyl); —SO₂NR₂₃₅R₂₄₀; —CO—NR₂₃₅R₂₄₀; —SO₂—(C₁-C₄ alkyl); and         ═O; wherein     -   R₂₁₅ at each occurrence is independently C₁-C₆ alkyl,         —(CH₂)₀₋₂—(phenyl), C₃-C₆ cycloalkyl, —(CH₂)₀₋₂-(pyridyl),         —(CH₂)₀₋₂-(pyrrolyl), —(CH₂)₀₋₂-(imidazolyl),         —(CH₂)₀₋₂-(pyrimidyl), —(CH₂)₀₋₂-(pyrrolidinyl),         —(CH₂)₀₋₂-(imidazolidinyl) —(CH₂)₀₋₂—(piperazinyl),         —(CH₂)₀₋₂—(piperidinyl), and —(CH₂)₀₋₂-(morpholinyl); wherein         the phenyl group at each occurrence is optionally substituted         with 1 or 2 groups that are independently R₂₀₅ or R₂₁₀; wherein         each heterocycloalkyl group at each occurrence is optionally         substituted with 1 or 2 R₂₁₀; wherein each heteroaryl group at         each occurrence is optionally substituted with 1 or 2 R₂₁₀;     -   R₂₂₀ and R₂₂₅ at each occurrence are independently —H, —C₁-C₄         alkyl, hydroxy C₁-C₄ alkyl, halo C₁-C₄ alkyl; —C₃-C₆ cycloalkyl,         and —(C₁-C₄ alkyl)-O—(C₁-C₂ alkyl)     -   R₂₃₅ and R₂₄₀ at each occurrence are independently H, or C₁-C₆         alkyl;     -   R₂₄₅ and R₂₅₀ at each occurrence are independently H, C₁-C₄         alkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, or     -   R₂₄₅ and R₂₅₀ are taken together with the carbon to which they         are attached to form a carbocycle of 3, 4, 5, or 6 carbon atoms.

Other preferred compounds of formula I-3 include compounds wherein

-   X is —C₁-C₃ alkylidenyl optionally optionally substituted with 1 or     2 methyl groups; -   Z is SO₂; SO; S; or C(O); -   Y is C₁-C₄ haloalkyl; OH; —N(Y₁) (Y₂); C₁-C₁₀alkyl optionally     substituted with 1 or 2 substituents which can be the same or     different and are selected from halogen, hydroxy, C₁-C₄ alkoxy,     C₁-C₄ thioalkoxy, and C₁-C₄ haloalkoxy; C₁-C₄ alkoxy; phenyl     optionally substituted with halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CN     or NO₂; and benzyl optionally substituted with halogen, C₁-C₄ alkyl,     C₁-C₄ alkoxy, CN or NO₂; wherein     -   Y₁ and Y₂ are the same or different and are H; C₁-C₆ alkyl         optionally substituted with 1, 2, or 3 substituents selected         from halogen, C₁-C₂ alkoxy, C₃-C₆ cycloalkyl, and OH; C₂-C₆         alkanoyl; phenyl; —SO₂—C₁-C₄ alkyl; benzyl; and C₃-C₆ cycloalkyl         C₁-C₂ alkyl; or     -   —N(Y₁) (Y₂) forms a ring selected from piperazinyl, piperidinyl,         morpholinyl, and pyrolidinyl, wherein each ring is optionally         substituted with 1, 2, 3, or 4 groups that are independently         C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, or halogen.

Preferred compounds of formula I-3 also include those of formula I-4, i.e., compounds of formula I-3 wherein

-   X is —C₁-C₃ alkylidenyl optionally optionally substituted with 1     methyl group; -   Z is SO₂; SO; S; or C(O); -   Y is OH; —N(Y₁) (Y₂); phenyl; benzyl; or C₁-C₁₀ alkyl optionally     substituted with 1 or 2 substituents which can be the same or     different and are selected from halogen, hydroxy, methoxy, ethoxy,     thiomethoxy, thioethoxy, and CF₃; wherein     -   Y₁ and Y₂ are the same or different and are H; C₁-C₄ alkyl         optionally substituted with 1 or 2 substituents selected from         halogen, methoxy, ethoxy, cyclopropyl, and OH; or     -   —N(Y₁) (Y₂) forms a ring selected from piperazinyl, piperidinyl,         morpholinyl, and pyrolidinyl, wherein each ring is optionally         substituted with 1 or 2 groups that are independently C₁-C₄         alkyl, C₁-C₄ alkoxy, or halogen; -   R₁ is benzyl which is optionally substituted with 1, 2, or 3 groups     independently selected from methyl, ethyl, n-propyl, isopropyl,     hydroxymethyl, monohalomethyl, dihalomethyl, trihalomethyl, —CH₂CF₃,     methoxymethyl, halogen, methoxy, ethoxy, n-propyloxy, isopropyloxy,     and OH; -   R₂ and R₃ are independently H or C₁-C₄ alkyl; -   R_(C) is C₁-C₆ alkyl optionally substituted with 1, 2, or 3 R₂₀₅     groups; cyclopropyl, cyclopropylmethyl, cyclopentyl,     cyclopentylmethyl, cyclohexyl, cyclohexylmethyl;     —(CR₂₄₅R₂₅₀)₀₋₃-phenyl optionally substituted with 1 or 2 R₂₀₀     groups; —(CR₂₄₅R₂₅₀)₀₋₃-pyridyl optionally substituted with 1 or 2     R₂₀₀; —(CR₂₄₅R₂₅₀)₀₋₃-piperazinyl; or (CR₂₄₅R₂₅₀)₀₋₃-pyrrolidinyl;     —(CR₂₄₅R₂₅₀)₀₋₃-piperidinyl; each of the above heterocycloalkyl     groups is optionally substituted with 1 or 2 R₂₁₀ groups;     -   R₂₀₀ at each occurrence is independently selected from C₁-C₄         alkyl optionally substituted with 1 or 2 R₂₀₅ groups; OH; and         halogen;     -   R₂₀₅ at each occurrence is independently selected from C₁-C₄         alkyl, halogen, —OH, —SH, C≡N, —CF₃, and C₁-C₄ alkoxy;     -   R₂₁₀ at each occurrence is independently selected from C₁-C₄         alkyl optionally substituted with 1 or 2 R₂₀₅ groups; halogen;         C₁-C₄ alkoxy; OCF₃; NH₂, NH(C₁-C₆ alkyl); N(C₁-C₆ alkyl) (C₁-C₆         alkyl); OH; and —CO—(C₁-C₄ alkyl); wherein     -   R₂₄₅ and R₂₅₀ at each occurrence are independently selected from         H, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, or     -   R₂₄₅ and R₂₅₀ are taken together with the carbon to which they         are attached to form a carbocycle of 3, 5, or 6 carbon atoms.

Preferred compounds of formulas I, I-1 and I-2 include compounds of formula I-5, i.e., those of formulae I, I-1 or I-2 wherein

-   R_(N) is —C(═O)—(CRR′)₀₋₆R₁₀₀; and -   R₁₀₀ represents aryl, heteroaryl, or heterocyclyl, where the ring     portions of each are optionally substituted with 1, 2, or 3 groups     independently selected from     -   —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,         —(CH₂)₀₋₄—O—P(═O) (OR) (OR′), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,         —(CH₂)₀O₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),         —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),         —(CH₂)₀₋₄—CO—(CH₂)₀₋₄ (C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R₁₁₀,         —(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀,         —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₄₀,         —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅,         —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂ (C₁-C₁₂ alkyl),         —(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇ cycloalkyl),         —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀, —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂,         —(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅,         —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₋₄—O—CO—(C₁-C₆         alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂, —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂,         —(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀),         —(CH₂)₀₋₄—O—R₁₀₅′—COOH, —(CH₂)₀₋₄—S—(R₁₅₀),         —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, (C₂-C₁₀)         alkenyl, or (C₂-C₁₀) alkynyl.

Preferred compounds of formula I-5 include compounds wherein

-   R_(N) is —C(═O)—R₁₀₀; and -   R₁₀₀ represents aryl, or heteroaryl, where the ring portions of each     are optionally substituted with 1, 2, or 3 groups independently     selected from     -   —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,         —(CH₂)₀₋₄—O—P(═O) (OR) (OR), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,         —(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R′₁₀₂, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),         —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),         —(CH₂)₀₋₄—CO—(CH₂)₀₋₄ (C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R₁₁₀,         —(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀,         —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₄₀,         —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅,         —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂(C₁-C₁₂ alkyl),         —(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇ cycloalkyl),         —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀, —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂,         —(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅,         —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₋₄—O—CO—(C₁-C₆         alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂, —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂,         —(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀),         —(CH₂)₀₋₄—O—R₁₅₀–—COOH, —(CH₂)₀₋₄—S—(R₁₅₀),         —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, —(CH₂)₀₋₄—C₃-C₇ cycloalkyl,         (C₂-C₁₀)alkenyl, or (C₂-C₁₀) alkynyl.

Preferred compounds of formula I-5 also include compounds wherein

-   R_(N) is —C(═O)-aryl or —C(═O)-heteroaryl where the ring portions of     each are optionally substituted with 1, 2, or 3 groups independently     selected from     -   —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,         —(CH₂)₀O₄—CO—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′,         —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl),         —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl), —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀,         —(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀, —(CH₂)₀₋₄—CO—R₁₂₀,         —(CH₂)₀₋₄—CO—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₄₀, —(CH₂)₀₋₄—CO—O—R₁₅o,         —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅—(CH₂)₀₋₄—SO—(C₁-C₈ alkyl),         —(CH₂)₀₋₄—SO₂ (C₁-C₁₂ alkyl), —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀,         —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅,         —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₋₄—O—CO—(C₁-C₆         alkyl), —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀),         —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, (C₂-C₁₀)         alkenyl, or (C₂-C₁₀) alkynyl.

Other preferred compounds of formula I-5 include compounds wherein

-   R_(N) is —C(═O)-aryl or —C(═O)-heteroaryl where the ring portions of     each are optionally substituted with 1 or 2 groups independently     selected from     -   C₁-C₆ alkyl, halogen, —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,         —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅,         —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅, C₃-C₇ cycloalkyl, (C₂-C₁₀) alkenyl,         —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀, or (C₂-C₁₀)         alkynyl.

Other preferred compounds of formula I-5 also include compounds wherein R_(N) is:

-   wherein sub is hydrogen or is C₁-C₆ alkyl, halogen,     —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂,     —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅ C₃-C₇     cycloalkyl, —(C₂-C₁₀) alkenyl, —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀,     —(CH₂)₀₋₄—R₁₃₀, or (C₂-C₁₀) alkynyl.

A preferred stereochemistry for compounds of formula I is as follows:

Preferred compounds of formula X include those of formula X-1, i.e., compounds of formula X wherein

-   R₁ is aryl, heteroaryl, heterocyclyl, —C₁-C₆ alkyl-aryl, —C₁-C₆     alkyl-heteroaryl, or —C₁-C₆ alkyl-heterocyclyl, where the ring     portions of each are optionally substituted with 1, 2, 3, or 4     groups independently selected from halogen, —OH, —SH, —C≡N, —NO₂,     —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′, or —N(R)SO₂R′, —C(═O)—(C₁-C₄) alkyl,     —SO₂-amino, —SO₂-mono or dialkylamino, —C(═O)-amino, —C(═O)-mono or     dialkylamino, —SO₂—(C₁-C₄) alkyl, or     -   C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups which         are independently selected from halogen, or     -   C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃         alkoxy, amino, —C₁-C₆ alkyl and mono- or dialkylamino, or     -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, —OH, —SH, —C≡N, —CF₃,         —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, or     -   C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally         substituted with 1, 2, or 3 groups independently selected from         halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl         and mono- or dialkylamino; and the heterocyclyl group is         optionally further substituted with oxo.

Preferred compounds of formula X-1 also include those wherein

-   R₁ is —C₁-C₆ alkyl-aryl, —C₁-C₆ alkyl-heteroaryl, or —C₁-C₆     alkyl-heterocyclyl, where the ring portions of each are optionally     substituted with 1, 2, 3, or 4 groups independently selected from     halogen, —OH, —SH, —C≡N, —NO₂, —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′, or     —N(R)SO₂R, —C(═O)—(C₁-C₄) alkyl, —SO₂-amino, —SO₂-mono or     dialkylamino, —C(═O)-amino, —C(═O)-mono or dialkylamino,     —SO₂—(C₁-C₄) alkyl, or     -   C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups which         are independently selected from halogen, or     -   C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃         alkoxy, amino, —C₁-C₆ alkyl and mono- or dialkylamino, or     -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, —OH, —SH, —C≡N, —CF₃,         —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, or     -   C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally         substituted with 1, 2, or 3 groups independently selected from         halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl         and mono- or dialkylamino; and the heterocyclyl group is         optionally further substituted with oxo.

Preferred compounds of formula X-1 further include those wherein

-   R₁ is —(CH₂)-aryl, —(CH₂)-heteroaryl, or —(CH₂)-heterocyclyl, where     the ring portions of each are optionally substituted with 1, 2, 3,     or 4 groups independently selected from halogen, —OH, —SH, —C≡N,     —NO₂, —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′, or —N(R)SO₂R, —C(═O)—(C₁-C₄)     alkyl, —SO₂-amino, —SO₂-mono or dialkylamino, —C(═O)-amino,     —C(═O)-mono or dialkylamino, —SO₂—(C₁-C₄) alkyl, or     -   C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups which         are independently selected from halogen, or     -   C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃         alkoxy, amino, —C₁-C₆ alkyl and mono- or dialkylamino, or     -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups         independently selected from halogen, —OH, —SH, —C≡N, —CF₃,         —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, or     -   C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally         substituted with 1, 2, or 3 groups independently selected from         halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl         and mono- or dialkylamino; and the heterocyclyl group is         optionally further substituted with oxo.

Preferred compounds of formula X-1 also include those wherein

-   R₁ is —CH₂-phenyl or —CH₂-pyridinyl where the ring portions of each     are optionally substituted with 1, 2, 3, or 4 groups independently     selected from halogen, C₁-C₄ alkoxy, hydroxy, —NO₂, and     -   C₁-C₄ alkyl optionally substituted with 1, 2, or 3 substituents         independently selected from halogen, OH, SH, NH₂, NH(C₁-C₆         alkyl), N—(C₁-C₆ alkyl) (C₁-C₆ alkyl), C≡N, CF₃.

Preferred compounds of formula X-1 further include those wherein

-   R₁ is —CH₂-phenyl or —CH₂-pyridinyl where the phenyl or pyridinyl     rings are each optionally substituted with 1 or 2 groups     independently selected from halogen, C₁-C₂ alkyl, C₁-C₂ alkoxy,     hydroxy, —CF₃, and —NO₂.

Preferred compounds of formula X-1 include those wherein

-   R₁ is —CH₂-phenyl where the phenyl ring is optionally substituted     with 2 groups independently selected from halogen, C₁-C₂ alkyl,     C₁-C₂ alkoxy, hydroxy, and —NO₂.

Preferred compounds of formula X-1 also include those wherein R₁ is benzyl, or 3,5-difluorobenzyl.

Preferred compounds of formula X or X-1 include those of formula X-2, i.e., compounds of formula X or X-1 wherein

-   R₂ and R₃ are independently selected from H or C₁-C₆ alkyl     optionally substituted with 1, 2, or 3 substituents selected from     the group consisting of C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃,     C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b).

Preferred compounds of formula X-2 include those wherein

-   R_(C) is selected from the group consisting of C₁-C₁₀ alkyl     optionally substituted with 1, 2, or 3 groups independently selected     from the group consisting of R₂₀₅, —OC═ONR₂₃₅R₂₄₀, —S(═O)O₂(C₁-C₆     alkyl), —SH, —NR₂₃₅C═ONR₂₃₅R₂₄₀—C═ONR₂₃₅R₂₄₀, and —S(═O)₂NR₂₃₅R₂₄₀;     —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl wherein the cycloalkyl is optionally     substituted with 1, 2, or 3 groups independently selected from the     group consisting of R₂₀₅, —CO₂H, and —CO₂—(C₁-C₄ alkyl);     —(CR₂₄₅R₂₅₀)₀₋₄-aryl; —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl;     —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl; —[C(R₂₅₅) (R₂₆₀)]₁₋₃—CO—N—(R₂₅₅)₂;     —CH(aryl)₂; —CH(heteroaryl)₂; —CH(heterocycloalkyl)₂; —CH(aryl)     (heteroaryl); —CO—NR₂₃₅R₂₄₀; —(CH₂)₀₋₁—CH((CH₂)₀₆—OH)—(CH₂)₀₋₁-aryl;     —(CH₂)₀₋₁—CHR_(C-6)—(CH₂)₀₋₁-heteroaryl; —CH(-aryl or     -heteroaryl)-CO—O(C₁-C₄ alkyl); —CH(—CH₂—OH)—CH(OH)-phenyl-NO₂;     (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-OH; —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂; —H;     and —(CH₂)₀₋₆—C(═NR₂₃₅) (NR₂₃₅R₂₄₀); wherein     -   each aryl is optionally substituted with 1, 2, or 3 R₂₀₀;     -   each heteroaryl is optionally substituted with 1, 2, 3, or 4         R₂₀₀;     -   each heterocycloalkyl is optionally substituted with 1, 2, 3, or         4 R₂₁₀;     -   R₂₀₀ at each occurrence is independently selected from the group         consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3         R₂₀₅ groups; OH; —NO₂; halogen; —CO₂H; C≡N;         —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl);         —(CH₂)₀₋₄—CO₂R₂₁₅; and —(CH₂)_(0-—) ₄—O—(C₁-C₆ alkyl optionally         substituted with 1, 2, 3, or 5-F);         -   wherein each aryl group at each occurrence is optionally             substituted with 1, 2, or 3 groups that are independently             R₂₀₅, R₂₁₀ or C₁-C₆ alkyl substituted with 1, 2, or 3 groups             that are independently R₂₀₅ or R₂₁₀;         -   wherein each heterocycloalkyl group at each occurrence is             optionally substituted with 1, 2, or 3 groups that are             independently R₂₁₀;         -   wherein each heteroaryl group at each occurrence is             optionally substituted with 1, 2, or 3 groups that are             independently R₂₀₅, R₂₁₀, or C₁-C₆ alkyl substituted with 1,             2, or 3 groups that are independently R₂₀₅ or R₂₁₀;     -   R₂₀₅ at each occurrence is independently selected from the group         consisting of C₁-C₆ alkyl, halogen, —OH, —O-phenyl, —SH, —C≡N,         —CF₃, C₁-C₆ alkoxy, NH₂, NH(C₁-C₆ alkyl), and N—-(C₁-C₆ alkyl)         (C₁-C₆ alkyl);     -   R₂₁₀ at each occurrence is independently selected from the group         consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3         R₂₀₅ groups; halogen; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy;         —NR₂₂₀R₂₂₅; OH; C≡N; C₃-C₇ cycloalkyl optionally substituted         with 1, 2, or 3 R₂₀₅ groups; —CO—(C₁-C₄ alkyl); SO₂—NR₂₃₅R₂₄₀;         —CO—NR₂₃₅R₂₄₀; —SO₂—(C₁-C₄ alkyl); and ═O; wherein     -   R₂₁₅ at each occurrence is independently selected from the group         consisting of C₁-C₆ alkyl, —(CH₂)₀₋₂-(aryl), C₃-C₇ cycloalkyl,         and —(CH₂)₀₋₂-(heteroaryl), —(CH₂)₀₋₂-(heterocycloalkyl);         wherein the aryl group at each occurrence is optionally         substituted with 1, 2, or 3 groups that are independently R₂₀₅         or R₂₁₀; wherein the heterocycloalkyl group at each occurrence         is optionally substituted with 1, 2, or 3 R₂₁₀; wherein each         heteroaryl group at each occurrence is optionally substituted         with 1, 2, or 3 R₂₁₀;     -   R₂₂₀ and R₂₂₅ at each occurrence are independently selected from         the group consisting of —H, —C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl,         amino C₁-C₆ alkyl; halo C₁-C₆ alkyl; —C₃-C₇ cycloalkyl, —(C₁-C₆         alkyl)-O—(C₁-C₃ alkyl), -aryl, -heteroaryl, and         -heterocycloalkyl; wherein the aryl group at each occurrence is         optionally substituted with 1, 2, or 3 R₂₇₀ groups, each         heteroaryl is optionally substituted with 1, 2, 3, or 4 R₂₀₀,         each heterocycloalkyl is optionally substituted with 1, 2, 3, or         4 R₂₁₀ wherein     -   R₂₇₀ at each occurrence is independently R₂₀₅, C₁-C₆ alkyl         optionally substituted with 1, 2, or 3 R₂₀₅ groups; halogen;         C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; NR₂₃₅R₂₄₀; OH; C≡N; —CO—(C₁-C₄         alkyl); and ═O; wherein the heterocycloalkyl group at each         occurrence is optionally substituted with 1, 2, or 3 R₂₀₅         groups; wherein each heteroaryl group at each occurrence is         optionally substituted with 1, 2, or 3 R₂₀₅ groups;     -   R₂₃₅ and R₂₄₀ at each occurrence are independently H, or C₁-C₆         alkyl;     -   R₂₄₅ and R₂₅₀ at each occurrence are independently selected from         the group consisting of H, C₁-C₄ alkyl, C₁-C₄ hydroxyalkyl,         C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, or     -   R₂₄₅ and R₂₅₀ are taken together with the carbon to which they         are attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon         atoms, wherein the carbocycle is optionally substituted with 1         or 2 groups that are independently OH, methyl, Cl, F, OCH₃, CF₃,         NO₂, or CN;     -   R₂₅₅ and R₂₆₀ at each occurrence are independently selected from         the group consisting of H; C₁-C₆ alkyl optionally substituted         with 1, 2, or 3 R₂₀₅ groups; —(CH₂)₀₋₄—C₃-C₇ cycloalkyl         optionally substituted with 1, 2, or 3 R₂₀₅ groups; —(C₁-C₄         alkyl)-aryl; —(C₁-C₄ alkyl)-heteroaryl; —(C₁-C₄         alkyl)-heterocycloalkyl; aryl; heteroaryl; heterocycloalkyl;         —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-aryl;         —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heteroaryl; and;         —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heterocycloalkyl; wherein         -   R₂₆₅ at each occurrence is independently —O—, —S— or             —N(C₁-C₆ alkyl)-;         -   each aryl or phenyl is optionally substituted with 1, 2, or             3 groups that are independently R₂₀₅, R₂₁₀, or C₁-C₆ alkyl             substituted with 1, 2, or 3 groups that are independently             R₂₀₅ or R₂₁₀.

Preferred compounds of formula X-2 include those wherein:

-   R_(C) is —(CR₂₄₅R₂₅₀)₀₋₄-aryl, or —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl,     wherein aryl and heteroaryl are optionally substituted with 1, 2, or     3 R₂₀₀ groups.

Preferred compounds of formula X-2 also include compounds wherein

-   R_(C) is —(CR₂₄₅R₂₅₀)-aryl, or —(CR₂₄₅R₂₅₀)-heteroaryl wherein each     aryl and heteroaryl is optionally substituted with 1, 2, or 3 R₂₀₀     groups.

Preferred compounds of formula X-2 also include compounds wherein

-   -   R_(C) is —(CH₂)-aryl, or —(CH₂)-heteroaryl, wherein     -   each aryl and heteroaryl is optionally substituted with 1, 2, or         3 groups selected from OH, —NO₂, halogen, —CO₂H, C≡N,         —(CH₂)₀₋₄—CO—NR₂₂OR₂₂₅, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), and         —(CH₂)₀₋₄—SO₂—NR₂₂OR₂₂₅.

Preferred compounds of formula X-2 also include compounds wherein

-   R_(C) is —(CH₂)-aryl, wherein aryl is optionally substituted with 1,     2, or 3 groups selected from OH, —NO₂, halogen, —CO₂H, and C—N.

Preferred compounds of formula X-2 also include compounds wherein

-   R_(C) is —(CH₂)-phenyl, wherein phenyl is optionally substituted     with 1, 2, or 3 groups selected from OH, —NO₂, halogen, —CO₂H, and     C≡N.

Preferred compounds of formula X-2 also include compounds wherein R_(C) is benzyl.

Other preferred compounds of formulas X, X-1 or X-2 include compounds of formula X-3, i.e., those of formulas X, X-1 or X-2 wherein

-   R_(N) is:

-   -   wherein

-   R₄ is NH₂; —NH—(CH₂),₆—R₄₋₁; —NHR₈; —NR₅₀C(O)R₅; or —NR₅₀CO₂R₅₁;     -   wherein         -   n₆ is 0, 1, 2, or 3;         -   n₇ is 0, 1, 2, or 3;     -   R₄₋₁ is selected from the group consisting of —SO₂—(C₁-C₈         alkyl), —SO—(C₁-C₈ alkyl), —S—(C₁-C₈-alkyl), —S—CO—(C₁-C₆         alkyl), —SO₂—NR₄₋₂R₄₋₃; —CO—C₁-C₂ alkyl; —CO—NR₄₋₃R₄₋₄;     -   R₄₋₂ and R₄₋₃ are independently H, C₁-C₃ alkyl, or C₃-C₆         cycloalkyl;     -   R₄₋₄ is alkyl, phenylalkyl, C₂-C₄ alkanoyl, or phenylalkanoyl;

-   R₅ is cyclopropyl; cyclobutyl; cyclopentyl; or cyclohexyl; wherein     each cycloalkyl group is optionally substituted with one or two     groups that are C₁-C₆ alkyl, more preferably C₁-C₂ alkyl, C₁-C₆     alkoxy, more preferably C₁-C₂ alkoxy, CF₃, OH, NH₂, NH(C₁-C₆ alkyl),     N(C₁-C₆ alkyl) (C₁-C₆ alkyl), halogen, CN, or NO₂; or the cycloalkyl     group is substituted with 1 or 2 groups that are independently CF₃,     Cl, F, methyl, ethyl or cyano; C₁-C₆ alkyl optionally substituted     with 1, 2, or 3 groups that are independently halogen, —NR₆R₇, C₁-C₄     alkoxy, C₅-C₆ heterocycloalkyl, C₅-C₆ heteroaryl, phenyl, C₃-C₇     cycloalkyl, —S—C₁-C₄ alkyl, —SO₂—C₁-C₄ alkyl, —CO₂H, —CONR₆R₇,     —CO₂—C₁-C₄ alkyl, or phenyloxy; heteroaryl optionally substituted     with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄     alkoxy, halogen, C₁-C₄ haloalkyl, or OH; heterocycloalkyl optionally     substituted with 1, 2, or 3 groups that are independently C₁-C₄     alkyl, C₁-C₄ alkoxy, halogen, or C₂-C₄ alkanoyl; phenyl optionally     substituted with 1, 2, 3, or 4 groups that are independently     halogen, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₁-C₄ haloalkyl; and     —NR₆R₇; wherein     -   R₆ and R₇ are independently selected from the group consisting         of H, C₁-C₆ alkyl, C₂-C₆ alkanoyl, phenyl, —SO₂—C₁-C₄ alkyl, and         phenyl C₁-C₄ alkyl;     -   R₈ is selected from the group consisting of —SO₂-heteroaryl         optionally substituted with 1 or 2 groups that are independently         C₁-C₄ alkyl or halogen;, —SO₂-aryl, —SO₂-heterocycloalkyl,         —C(O)NHR₉, heterocycloalkyl, —S—C₂-C₄ alkanoyl, wherein         -   R₉ is phenyl C₁-C₄ alkyl, C₁-C₆ alkyl, or H; R₅₀ is H or             C₁-C₆ alkyl;     -   R₅₁ is selected from the group consisting of phenyl C₁-C₄ alkyl;         C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that         are independently halogen, cyano, —NR₆R₇, —C(O)NR₆R₇, C₃-C₇ or         —C₁-C₄ alkoxy; heterocycloalkyl optionally substituted with 1 or         2 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, C₂-C₄ alkanoyl, phenyl C₁-C₄ alkyl, and —SO₂ C₁-C₄         alkyl; heterocycloalkylalkyl optionally substituted with 1 or 2         groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, C₂-C₄ alkanoyl, phenyl C₁-C₄ alkyl, and —SO₂ C₁-C₄         alkyl; alkenyl; alkynyl; heteroaryl optionally substituted with         1, 2, or 3 groups that are independently OH, C₁-C₄ alkyl, C₁-C₄         alkoxy, halogen, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆         alkyl); heteroarylalkyl optionally substituted with 1, 2, or 3         groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl);         phenyl; C₃-C₈ cycloalkyl, and cycloalkylalkyl, wherein the         phenyl; C₃-C₈ cycloalkyl, and cycloalkylalkyl groups are         optionally substituted with 1, 2, 3, 4 or 5 groups that are         independently halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆         alkanoyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, hydroxy, C₁-C₆         hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ thioalkoxy, C₁-C₆         thioalkoxy C₁-C₆ alkyl, or C₁-C₆ alkoxy C₁-C₆ alkoxy.

Preferred compounds of formula X-3 include compounds wherein

-   R_(N) is

-   -   wherein

-   X is C₁-C₄ alkylidenyl optionally substituted with 1, 2, or 3 methyl     groups; or —NR₄₋₆—; or     -   R₄ and R₄₋₆ combine to form —(CH₂)_(n10)—, wherein n₁₀ is 1, 2,         3, or 4;

-   Z is selected from a bond; SO₂; SO; S; and C(O);

-   Y is selected from H; C₁-C₄ haloalkyl; C₅-C₆ heterocycloalkyl     containing at least one N, O, or S; phenyl; OH; —N(Y₁) (Y₂); C₁-C₁₀     alkyl optionally substituted with 1 thru 3 substituents which can be     the same or different and are selected from halogen, hydroxy,     alkoxy, thioalkoxy, and haloalkoxy; C₃-C₈ cycloalkyl optionally     substituted with 1, 2, or 3 groups independently selected from C₁-C₃     alkyl, and halogen; alkoxy; phenyl optionally substituted with     halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CN or NO₂; phenyl C₁-C₄ alkyl     optionally substituted with halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CN     or NO₂; wherein     -   Y₁ and Y₂ are the same or different and are H; C₁-C₁₀ alkyl         optionally substituted with 1, 2, or 3 substituents selected         from the group consisting of halogen, C₁-C₄ alkoxy, C₃-C₈         cycloalkyl, and OH; C₂-C₆ alkenyl; C₂-C₆ alkanoyl; phenyl;         —SO₂—C₁-C₄ alkyl; phenyl C₁-C₄ alkyl; and C₃-C₈ cycloalkyl C₁-C₄         alkyl; or     -   —N(Y₁) (Y₂) forms a ring selected from piperazinyl, piperidinyl,         morpholinyl, and pyrolidinyl, wherein each ring is optionally         substituted with 1, 2, 3, or 4 groups that are independently         C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, or halogen.

Preferred compounds of formula X-3 include compounds wherein

-   X is C₁-C₄ alkylidenyl optionally substituted with 1, 2, or 3 methyl     groups; -   Z is selected from SO₂; SO; S; and C(O); -   Y is selected from H; C₁-C₄ haloalkyl; C₅-C₆ heterocycloalkyl     containing at least one N, O, or S; phenyl; OH; —N(Y₁) (Y₂); C₁-C₁₀     alkyl optionally substituted with 1 thru 3 substituents which can be     the same or different and are selected from the group consisting of     halogen, hydroxy, alkoxy, thioalkoxy, and haloalkoxy; C₃-C₈     cycloalkyl optionally substituted with 1, 2, or 3 groups     independently selected from C₁-C₃ alkyl, and halogen; alkoxy; phenyl     optionally substituted with halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CN     or NO₂; phenyl C₁-C₄ alkyl optionally substituted with halogen,     C₁-C₄ alkyl, C₁-C₄ alkoxy, CN or NO₂; wherein     -   Y₁ and Y₂ are the same or different and are H; C₁-C₆ alkyl         optionally substituted with 1, 2, or 3 substituents selected         from the group consisting of halogen, C₁-C₄ alkoxy, C₃-C₈         cycloalkyl, and OH; C₂-C₆ alkenyl; C₂-C₆ alkanoyl; phenyl;         —SO₂—C₁-C₄ alkyl; phenyl C₁-C₄ alkyl; or C₃-C₈ cycloalkyl C₁-C₄         alkyl; or     -   —N(Y₁) (Y₂) forms a ring selected from piperazinyl, piperidinyl,         morpholinyl, and pyrolidinyl, wherein each ring is optionally         substituted with 1, 2, 3, or 4 groups that are independently         C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, or halogen.

Preferred compounds of formula X-3 include compounds wherein R_(N) is

-   -   and wherein R₄ is NH₂; —NH—(CH₂)_(n6)—R₄₋₁; —NHR₈; —NR₅₀C(O)R₅;         or —NR₅₀CO₂R₅₁ wherein         -   n₆ is 0, 1, 2, or 3;         -   n₇ is 0, 1, 2, or 3;     -   R₄₋₁ is selected from the group consisting of —SO₂—(C₁-C₈         alkyl), —SO—(C₁-C₈ alkyl), —S—(C₁-C₈ alkyl), —S—CO—(C₁-C₆         alkyl), —SO₂—NR₄₋₂R₄₋₃; —CO—C₁-C₂ alkyl; —CO—NR₄₋₃R₄₋₄;     -   R₄₋₂ and R₄₋₃ are independently H, C₁-C₃ alkyl, or C₃-C₆         cycloalkyl;     -   R₄₋₄ is alkyl, phenylalkyl, C₂-C₄ alkanoyl, or phenylalkanoyl;     -   R₅ is cyclopropyl; cyclobutyl; cyclopentyl; or cyclohexyl;         wherein each cycloalkyl group is optionally substituted with one         or two groups that are C₁-C₆ alkyl, more preferably C₁-C₂ alkyl,         C₁-C₆ alkoxy, more preferably C₁-C₂ alkoxy, CF₃, OH, NH₂,         NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl) (C₁-C₆ alkyl), halogen, CN, or         NO₂; or the cycloalkyl group is substituted with 1 or 2 groups         that are independently CF₃, Cl, F, methyl, ethyl or cyano; C₁-C₆         alkyl optionally substituted with 1, 2, or 3 groups that are         independently halogen, —NR₆R₇, C₁-C₄ alkoxy, C₅-C₆         heterocycloalkyl, C₅-C₆ heteroaryl, phenyl, C₃-C₇ cycloalkyl,         —S—C₁-C₄ alkyl, —SO₂—C₁-C₄ alkyl, —CO₂H, —CONR₆R₇, —CO₂—C₁-C₄         alkyl, or phenyloxy; heteroaryl optionally substituted with 1,         2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, C₁-C₄ haloalkyl, or OH; heterocycloalkyl optionally         substituted with 1, 2, or 3 groups that are independently C₁-C₄         alkyl, C₁-C₄ alkoxy, halogen, or C₂-C₄ alkanoyl; phenyl         optionally substituted with 1, 2, 3, or 4 groups that are         independently halogen, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₁-C₄         haloalkyl; and —NR₆R₇; wherein     -   R₆ and R₇ are independently selected from the group consisting         of H, C₁-C₆ alkyl, C₂-C₆ alkanoyl, phenyl, —SO₂—C₁-C₄ alkyl, and         phenyl C₁-C₄ alkyl;     -   R₈ is selected from the group consisting of —SO₂-heteroaryl         optionally substituted with 1 or 2 groups that are independently         C₁-C₄ alkyl or halogen;, —SO₂-aryl, —SO₂-heterocycloalkyl,         —C(O)NHR₉, heterocycloalkyl, —S—C₂-C₄ alkanoyl, wherein         -   R₉ is phenyl C₁-C₄ alkyl, C₁-C₆ alkyl, or H; R₅₀ is H or             C₁-C₆ alkyl; and     -   R₅₁ is selected from the group consisting of phenyl C₁-C₄ alkyl;         C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that         are independently halogen, cyano, —NR₆R₇, —C(O)NR₆R₇, C₃-C₇ or         —C₁-C₄ alkoxy; heterocycloalkyl optionally substituted with 1 or         2 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, C₂-C₄ alkanoyl, phenyl C₁-C₄ alkyl, and —SO₂ C₁-C₄         alkyl; heterocycloalkylalkyl optionally substituted with 1 or 2         groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, C₂-C₄ alkanoyl, phenyl C₁-C₄ alkyl, and —SO₂ C₁-C₄         alkyl; alkenyl; alkynyl; heteroaryl optionally substituted with         1, 2, or 3 groups that are independently OH, C₁-C₄ alkyl, C₁-C₄         alkoxy, halogen, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆         alkyl); heteroarylalkyl optionally substituted with 1, 2, or 3         groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,         halogen, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl);         phenyl; C₃-C₈ cycloalkyl, and cycloalkylalkyl, wherein the         phenyl; C₃-C₈ cycloalkyl, and cycloalkylalkyl groups are         optionally substituted with 1, 2, 3, 4 or 5 groups that are         independently halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆         alkanoyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, hydroxy, C₁-C₆         hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ thioalkoxy, C₁-C₆         thioalkoxy C₁-C₆ alkyl, or C₁-C₆ alkoxy C₁-C₆ alkoxy; and

-   Y is C₁-C₁₀ alkyl optionally substituted with 1 thru 3 substituents     which can be the same or different and are selected from halogen,     hydroxy, alkoxy, thioalkoxy, and haloalkoxy.

Preferred compounds of formula X-3 further include compounds wherein

-   R_(C) is C₁-C₈ alkyl optionally substituted with 1, 2, or 3 groups     independently selected from the group consisting of R₂₀₅,     —OC═ONR₂₃₅R₂₄₀, —S(═O)₀₋₂(C₁-C₆ alkyl), —SH, —C═ONR₂₃₅R₂₄₀, and     —S(═O)₂NR₂₃₅R₂₄₀; —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl wherein the     cycloalkyl is optionally substituted with 1, 2, or 3 groups     independently selected from the group consisting of R₂₀₅, —CO₂H, and     —CO₂—(C₁-C₄ alkyl); —(CR₂₄₅R₂₅₀)₀₋₄-phenyl;     —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl; —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl;     —(CH₂)₀₋₁—CH((CH₂)₀₋₄—OH)—(CH₂)₀₋₁-phenyl;     —(CH₂)₀₋₁—CHR_(C-6)—(CH₂)₀₋₁-heteroaryl;     —CH(—CH₂—OH)—CH(OH)-phenyl-NO₂; (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-OH; or     —(CH₂)₀₋₆—C(═NR₂₃₅)(NR₂₃₅R₂₄₀); wherein     -   each aryl is optionally substituted with 1, 2, or 3 R₂₀₀;     -   each heteroaryl is optionally substituted with 1, 2, 3, or 4         R₂₀₀;     -   each heterocycloalkyl is optionally substituted with 1, 2, 3, or         4 R₂₁₀;     -   R₂₀₀ at each occurrence is independently C₁-C₆ alkyl optionally         substituted with 1, 2, or 3 R₂₀₅ groups; OH; —NO₂; halogen;         —CO₂H; C≡N; —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl);         —(CH₂)₀₋₄—CO₂R₂₁₅; or —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally         substituted with 1, 2, 3, or 5-F);     -   R₂₀₅ at each occurrence is independently C₁-C₆ alkyl, halogen,         —OH, —O-phenyl, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, NH₂, NH(C₁-C₆         alkyl), or N—(C₁-C₆ alkyl) (C₁-C₆ alkyl);     -   R₂₁₀ at each occurrence is independently C₁-C₆ alkyl optionally         substituted with 1, 2, or 3 R₂₀₅ groups; halogen; C₁-C₆ alkoxy;         C₁-C₆ haloalkoxy; —NR₂₂₀R₂₂₅; OH; C≡N; C₃-C₇ cycloalkyl         optionally substituted with 1, 2, or 3 R₂₀₅ groups; —CO—(C₁-C₄         alkyl); SO₂NR₂₃₅R₂₄₀; —CO—NR₂₃₅R₂₄₀; —SO₂—(C₁-C₄ alkyl); and ═O;         wherein     -   R₂₁₅ at each occurrence is independently C₁-C₆ alkyl,         —(CH₂)₀₋₂-(phenyl), C₃-C₇ cycloalkyl, and         —(CH₂)₀₋₂-(heteroaryl), —(CH₂)₀₋₂-(heterocycloalkyl); wherein         the phenyl group at each occurrence is optionally substituted         with 1, 2, or 3 groups that are independently R₂₀₅ or R₂₁₀;         wherein the heterocycloalkyl group at each occurrence is         optionally substituted with 1, 2, or 3 R₂₁₀; wherein each         heteroaryl group at each occurrence is optionally substituted         with 1, 2, or 3 R₂₁₀;     -   R₂₂₀ and R₂₂₅ at each occurrence are independently —H, —C₁-C₆         alkyl, hydroxy C₁-C₆ alkyl, halo C₁-C₆ alkyl; —C₃-C₇ cycloalkyl,         and —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl);     -   R₂₃₅ and R₂₄₀ at each occurrence are independently H, or C₁-C₆         alkyl;     -   R₂₄₅ and R₂₅₀ at each occurrence are independently H, C₁-C₄         alkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, or     -   R₂₄₅ and R₂₅₀ are taken together with the carbon to which they         are attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon         atoms.

Preferred compounds of formula X-3 include compounds wherein

-   R₁ is benzyl which is optionally substituted with 1, 2, 3, or 4     groups independently selected from halogen, C₁-C₄ alkoxy, hydroxy,     and C₁-C₄ alkyl optionally substituted with 1, 2, or 3 substituents     halogen, OH, SH, NH₂, NH(C₁-C₆ alkyl), N—(C₁-C₆ alkyl) (C₁-C₆     alkyl), C≡N, CF₃; -   R₂ and R₃ are independently selected from H or C₁-C₄ alkyl     optionally substituted with 1 substituent selected from halogen,     —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, NH₂, NH(C₁-C₆ alkyl), and     NH(C₁-C₆ alkyl) (C₁-C₆ alkyl); -   R_(C) is C₁-C₈ alkyl optionally substituted with 1, 2, or 3 groups     independently selected from R₂₀₅, —SH, —C═ONR₂₃₅R₂₄₀, and     —S(═O)₂NR₂₃₅R₂₄₀; —(CH₂)₀₋₃—(C₃-C₆) cycloalkyl wherein the     cycloalkyl is optionally substituted with 1, 2, or 3 groups     independently selected from R₂₀₅, —CO₂H, and —CO₂—(C₁-C₄ alkyl);     —(CR₂₄₅R₂₅₀)₀₋₄-phenyl optionally substituted with 1, 2, or 3 R₂₀₀;     —(CR₂₄₅R₂₅₀)₀₋₃-pyridyl; —(CR₂₄₅R₂₅₀)₀₋₃-pyridazinyl;     —(CR₂₄₅R₂₅₀)₀₋₃-pyrimidinyl; —(CR₂₄₅R₂₅₀)₀₋₃-pyrazinyl;     —(CR₂₄₅R₂₅₀)₀₋₃-furyl; —(CR₂₄₅R₂₅₀)₀₋₃-indolyl;     —(CR₂₄₅R₂₅₀)₀₋₃-thienyl; —(CR₂₄₅R₂₅₀)₀₋₃-pyrrolyl;     —(CR₂₄₅R₂₅₀)₀₋₃-pyrazolyl; (CR₂₄₅R₂₅₀)₀₋₃-benzoxazolyl;     —(CR₂₄₅R₂₅₀)₀₋₃-imidazolyl; each of the above heteroaryl groups is     optionally substituted with 1, 2, 3, or 4 R₂₀₀;     —(CR₂₄₅R₂₅₀)₀₋₃-iimidazolidinyl; (CR₂₄₅R₂₅₀)₀₋₃-tetrahydrofuryl;     (CR₂₄₅R₂₅₀)₀₋₃-tetrahydropyranyl; (CR₂₄₅R₂₅₀)₀₋₃-piperazinyl;     (CR₂₄₅R₂₅₀)₀₋₃-pyrrolidinyl; (CR₂₄₅R₂₅₀)₀₋₃-piperidinyl;     (CR₂₄₅R₂₅₀)₀₋₃-indolinyl; each of the above heterocycloalkyl groups     is optionally substituted with 1, 2, 3, or 4 R₂₁₀;     (CH₂)₀₋₁—CH((CH₂)₀₋₄—OH)—(CH₂)₀₋₁-phenyl; —(CH₂)₀₋₁—CH(C₁-C₄     hydroxyalkyl)-(CH₂)₀₋₁-pyridyl;     -   R₂₀₀ at each occurrence is independently C₁-C₆ alkyl optionally         substituted with 1, 2, or 3 R₂₀₅ groups; OH; —NO₂; halogen;         —CO₂H; C≡N; —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—CO—(C₁-C₈ alkyl);         —(CH₂)₀₋₄—CO₂R₂₁₅; and —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally         substituted with 1, 2, 3, or 5-F);     -   R₂₀₅ at each occurrence is independently C₁-C₆ alkyl, halogen,         —OH, —O-phenyl, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, NH₂, NH(C₁-C₆         alkyl), and N—(C₁-C₆ alkyl) (C₁-C₆ alkyl);     -   R₂₁₀ at each occurrence is independently C₁-C₆ alkyl optionally         substituted with 1 or 2 R₂₀₅ groups; halogen; C₁-C₄ alkoxy;         C₁-C₄ haloalkoxy; —NR₂₂₀R₂₂₅; OH; C≡N; C₃-C₇ cycloalkyl         optionally substituted with 1 or 2 R₂₀₅ groups; —CO—(C₁-C₄         alkyl); SO₂NR₂₃₅R₂₄₀; —CO—NR₂₃₅R₂₄₀; —SO₂—(C₁-C₄ alkyl); and ═O;         wherein     -   R₂₁₅ at each occurrence is independently C₁-C₆ alkyl,         —(CH₂)₀₋₂-(phenyl), C₃-C₆ cycloalkyl, —(CH₂)₀₋₂-(pyridyl),         —(CH₂)₀₋₂—(pyrrolyl), —(CH₂)₀₋₂-(imidazolyl),         —(CH₂)₀₋₂-(pyrimidyl), —(CH₂)₀₋₂-(pyrrolidinyl),         —(CH₂)₀₋₂-(imidazolidinyl) —(CH₂)₀₋₂-(piperazinyl),         —(CH₂)₀₋₂-(piperidinyl), and —(CH₂)₀₋₂-(morpholinyl); wherein         the phenyl group at each occurrence is optionally substituted         with 1 or 2 groups that are independently R₂₀₅ or R₂₁₀; wherein         each heterocycloalkyl group at each occurrence is optionally         substituted with 1 or 2 R₂₁₀; wherein each heteroaryl group at         each occurrence is optionally substituted with 1 or 2 R₂₁₀;     -   R₂₂₀ and R₂₂₅ at each occurrence are independently —H, —C₁-C₄         alkyl, hydroxy C₁-C₄ alkyl, halo C₁-C₄ alkyl; —C₃-C₆ cycloalkyl,         and —(C₁-C₄ alkyl)-O—(C₁-C₂ alkyl);     -   R₂₃₅ and R₂₄₀ at each occurrence are independently H, or C₁-C₆         alkyl;     -   R₂₄₅ and R₂₅₀ at each occurrence are independently H, C₁-C₄         alkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, or     -   R₂₄₅ and R₂₅₀ are taken together with the carbon to which they         are attached to form a carbocycle of 3, 4, 5, or 6 carbon atoms.

Other preferred compounds of formula X-3 include compounds wherein

-   X is —C₁-C₃ alkylidenyl optionally optionally substituted with 1 or     2 methyl groups; -   Z is SO₂; SO; S; or C(O); -   Y is C₁-C₄ haloalkyl; OH; —N(Y) (Y₂); C₁-C₁₀ alkyl optionally     substituted with 1 or 2 substituents which can be the same or     different and are selected from halogen, hydroxy, C₁-C₄ alkoxy,     C₁-C₄ thioalkoxy, and C₁-C₄ haloalkoxy; C₁-C₄ alkoxy; phenyl     optionally substituted with halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CN     or NO₂; and benzyl optionally substituted with halogen, C₁-C₄ alkyl,     C₁-C₄ alkoxy, CN or NO₂; wherein     -   Y₁ and Y₂ are the same or different and are H; C₁-C₆ alkyl         optionally substituted with 1, 2, or 3 substituents selected         from halogen, C₁-C₂ alkoxy, C₃-C₆ cycloalkyl, and OH; C₂-C₆         alkanoyl; phenyl; —SO₂—C₁-C₄ alkyl; benzyl; and C₃-C₆ cycloalkyl         C₁-C₂ alkyl; or     -   —N(Y₁) (Y₂) forms a ring selected from piperazinyl, piperidinyl,         morpholinyl, and pyrolidinyl, wherein each ring is optionally         substituted with 1, 2, 3, or 4 groups that are independently         C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, or halogen.

Preferred compounds of formula X-3 also include those of formula X-4, i.e., compounds of formula X-3 wherein

-   X is —C₁-C₃ alkylidenyl optionally optionally substituted with 1     methyl group; -   Z is SO₂; SO; S; or C(O); -   Y is OH; —N(Y₁)(Y₂); phenyl; benzyl; or C₁-C₁₀ alkyl optionally     substituted with 1 or 2 substituents which can be the same or     different and are selected from halogen, hydroxy, methoxy, ethoxy,     thiomethoxy, thioethoxy, and CF₃; wherein     -   Y₁ and Y₂ are the same or different and are H; C₁-C₄ alkyl         optionally substituted with 1 or 2 substituents selected from         halogen, methoxy, ethoxy, cyclopropyl, and OH; or     -   —N(Y₁)(Y₂) forms a ring selected from piperazinyl, piperidinyl,         morpholinyl, and pyrolidinyl, wherein each ring is optionally         substituted with 1 or 2 groups that are independently C₁-C₄         alkyl, C₁-C₄ alkoxy, or halogen; -   R₁ is benzyl which is optionally substituted with 1, 2, or 3 groups     independently selected from methyl, ethyl, n-propyl, isopropyl,     hydroxymethyl, monohalomethyl, dihalomethyl, trihalomethyl, —CH₂CF₃,     methoxymethyl, halogen, methoxy, ethoxy, n-propyloxy, isopropyloxy,     and OH; -   R₂ and R₃ are independently H or C₁-C₄ alkyl; -   R_(C) is C₃-C₆ alkyl optionally substituted with 1, 2, or 3 R₂₀₅     groups; cyclopropyl, cyclopropylmethyl, cyclopentyl,     cyclopentylmethyl, cyclohexyl, cyclohexylmethyl;     —(CR₂₄₅R₂₅₀)₀₋₃-phenyl optionally substituted with 1 or 2 R₂₀₀     groups; —(CR₂₄₅R₂₅₀)₀₋₃-pyridyl optionally substituted with 1 or 2     R₂₀₀; —(CR₂₄₅R₂₅₀)₀₋₃-piperazinyl; or (CR₂₄₅R₂₅₀)₀₋₃-pyrrolidinyl;     —(CR₂₄₅R₂₅₀)₀₋₃-piperidinyl; each of the above heterocycloalkyl     groups is optionally substituted with 1 or 2 R₂₁₀ groups;     -   R₂₀₀ at each occurrence is independently selected from C₁-C₄         alkyl optionally substituted with 1 or 2 R₂₀₅ groups; OH; and         halogen;     -   R₂₀₅ at each occurrence is independently selected from C₁-C₄         alkyl, halogen, —OH, —SH, —C≡N, —CF₃, and C₁-C₄ alkoxy;     -   R₂₁₀ at each occurrence is independently selected from C₁-C₄         alkyl optionally substituted with 1 or 2 R₂₀₅ groups; halogen;         C₁-C₄ alkoxy; OCF₃; NH₂, NH(C₁-C₆ alkyl); N(C₁-C₆ alkyl) (C₁-C₆         alkyl); OH; and —CO—(C₁-C₄ alkyl); wherein     -   R₂₄₅ and R₂₅₀ at each occurrence are independently selected from         H, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, or     -   R₂₄₅ and R₂₅₀ are taken together with the carbon to which they         are attached to form a carbocycle of 3, 5, or 6 carbon atoms.

Preferred compounds of formulas X, X-1 and X-2 include compounds of formula X-5, i.e., those of formulae X, X-1 or X-2 wherein

-   R_(N) is —C(═O)—(CRR′)₀₋₆R₁₀₀; and -   R₁₀₀ represents aryl, heteroaryl, or heterocyclyl, where the ring     portions of each are optionally substituted with 1, 2, or 3 groups     independently selected from     -   —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,         —(CH₂)₀₋₄-O—P(═O) (OR) (OR), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,         —(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′, —(CH₂)_(0-4-CO—(C) ₁-C₁₂         alkyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂         alkynyl), —(CH₂)₀₋₄—CO—(CH₂)₀₋₄(C₃-C₇ cycloalkyl),         —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀,         —(CH₂)₀₋₄—CO—R₁₁₀, —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀,         —(CH₂)₀₋₄—CO—R₁₄₀, —(CH₂)₀₋₄—CO—O—R₁₅₀,         —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl),         —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl), —(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇         cycloalkyl), —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀,         —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂,         —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅, —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀,         —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂,         —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂,         —(CH₂)₀₋₄—O—(R₁₅₀), (CH₂)₀₋₄—O—R₁₅₀—COOH, —(CH₂)₀₋₄—S—(R₁₅₀),         —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, —(CH₂)₀₋₄—C₃-C₇ cycloalkyl,         (C₂-C₁₀)alkenyl, or (C₂-C₁₀)alkynyl.

Preferred compounds of formula X-5 include compounds wherein

-   R_(N) is —C(═O)—R₁₀₀; and -   R₁₀₀ represents aryl, or heteroaryl, where the ring portions of each     are optionally substituted with 1, 2, or 3 groups independently     selected from     -   —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,         —(CH₂)₀₋₄—O—P(═O) (OR) (OR), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,         —(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′—(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),         —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),         —(CH₂)₀₋₄—CO—(CH₂)₀₋₄ (C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R₁₁₀,         —(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀,         —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀, —(CH₂)₀O₄—CO—R₁₄₀,         —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₁₀,         —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂ (C₁-C₁₂ alkyl),         —(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇ cycloalkyl),         —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀, —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂,         —(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₀₅,         —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₋₄—O—CO—(C₁-C₆         alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂, —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂,         —(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀),         —(CH₂)₀₋₄—O—R₁₅₀′-COOH, —(CH₂)₀₋₄—S—(R₁₅₀),         —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅—(CH₂)₀₋₄—C₃-C₇ cycloalkyl,         (C₂-C₁₀)alkenyl, or (C₂-C₁₀)alkynyl.

Preferred compounds of formula X-5 also include compounds wherein

-   R_(N) is —C(═O)-aryl or —C(═O)-heteroaryl where the ring portions of     each are optionally substituted with 1, 2, or 3 groups independently     selected from     -   —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,         —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,         —(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′—(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),         —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),         —(CH₂)₀₋₄—R₁₁₀—(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀,         —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₄₀,         —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅,         —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂ (C₁-C₁₂ alkyl),         —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀, —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂,         —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅, —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀,         —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl), —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂,         —(CH₂)₀₋₄—O—(R₁₅₀), —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, —(CH₂)₀₋₄—C₃-C₇         cycloalkyl, (C₂-C₁₀)alkenyl, or (C₂-C₁₀)alkynyl.

Other preferred compounds of formula X-5 include compounds wherein

-   R_(N) is —C(═O)-aryl or —C(═O)-heteroaryl where the ring portions of     each are optionally substituted with 1 or 2 groups independently     selected from     -   C₁-C₆ alkyl, halogen, —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,         —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅,         —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅, C₃-C₇ cycloalkyl, (C₂-C₁₀) alkenyl,         —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀, or (C₂-C₁₀)         alkynyl.

Other preferred compounds of formula X-5 also include compounds wherein R_(N) is:

-   -   wherein sub is hydrogen or is C₁-C₆ alkyl, halogen,         —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,         —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂—(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅,         —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅, C₃-C₇ cycloalkyl, —(C₂-C₁₀)alkenyl,         —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀, or (C₂-C₁₀)         alkynyl.

A preferred stereochemistry for compounds of formula X is as follows:

In another aspect, the invention provides intermediates of the formula (IA):

wherein R₁, R₂, R₃, R_(N), and R_(C) are as defined above for compounds of formula I, and PROT is an amine protecting group as defined below.

In another aspect, the invention provides intermediates of the formula (XA):

wherein R₁, R₂, R₃, R_(N), and R_(C) are as defined above for compounds of formula I, and PROT is an amine protecting group as defined below

The invention also provides methods of generating compounds of formula (Y) from the compounds of formula (AA), formula (I) or formula (X), which are useful for treating and/or preventing Alzheimer's disease. The generation of compounds of formula (Y) from compounds of formulae (AA), (I) or (X) can occur in vivo or in vitro.

The invention also provides processes for converting compounds of formula AA, I or X to the compounds of formula Y by exposing compounds of formula AA, I or X to aqueous media. The conversion can occur in vitro or in vivo.

The invention also provides methods for treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, or diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which includes administration of a therapeutically effective amount of a compound of formula (AA), (I) or (X) or a pharmaceutically acceptable salts thereof.

In an embodiment, this method of treatment can be used where the disease is Alzheimer's disease.

In an embodiment, this method of treatment can help prevent or delay the onset of Alzheimer's disease.

In an embodiment, this method of treatment can be used where the disease is mild cognitive impairment.

In an embodiment, this method of treatment can be used where the disease is Down's syndrome.

In an embodiment, this method of treatment can be used where the disease is Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type.

In an embodiment, this method of treatment can be used where the disease is cerebral amyloid angiopathy.

In an embodiment, this method of treatment can be used where the disease is degenerative dementias.

In an embodiment, this method of treatment can be used where the disease is diffuse Lewy body type of Alzheimer's disease.

In an embodiment, this method of treatment can treat an existing disease.

In an embodiment, this method of treatment can prevent a disease from developing.

In an embodiment, this method of treatment can employ therapeutically effective amounts: for oral administration from about 0.1 mg/day to about 1,000 mg/day; for parenteral, sublingual, intranasal, intrathecal administration from about 0.5 to about 100 mg/day; for depo administration and implants from about 0.5 mg/day to about 50 mg/day; for topical administration from about 0.5 mg/day to about 200 mg/day; for rectal administration from about 0.5 mg to about 500 mg.

In an embodiment, this method of treatment can employ therapeutically effective amounts: for oral administration from about 1 mg/day to about 100 mg/day; and for parenteral administration from about 5 to about 50 mg daily.

In an embodiment, this method of treatment can employ therapeutically effective amounts for oral administration from about 5 mg/day to about 50 mg/day.

The invention also includes pharmaceutical compositions which include a compound of formula (AA), (I) or (X) or a pharmaceutically acceptable salts thereof.

The invention also includes the use of a compound of formula (AA), (I) or (X) or pharmaceutically acceptable salts thereof for the manufacture of a medicament.

The invention also includes methods for inhibiting beta-secretase activity, for inhibiting cleavage of amyloid precursor protein (APP), in a reaction mixture, at a site between Met596 and Asp597, numbered for the APP-695 amino acid isotype, or at a corresponding site of an isotype or mutant thereof; for inhibiting production of amyloid beta peptide (A beta) in a cell; for inhibiting the production of beta-amyloid plaque in an animal; and for treating or preventing a disease characterized by beta-amyloid deposits in the brain. These methods each include administration of a therapeutically effective amount of a compound of formula (AA), (I) or (X) or a pharmaceutically acceptable salts thereof.

The invention also includes a method for inhibiting beta-secretase activity, including exposing said beta-secretase to a compound of formula (AA), (I) or (X), under conditions whereby an effective inhibitory amount of a compound of formula (Y), or a pharmaceutically acceptable salt thereof, is formed.

In an embodiment, this method employs a compound that inhibits 50% of the enzyme's activity at a concentration of less than 50 micromolar.

In an embodiment, this method employs a compound that inhibits 50% of the enzyme's activity at a concentration of 10 micromolar or less.

In an embodiment, this method employs a compound that inhibits 50% of the enzyme's activity at a concentration of 1 micromolar or less.

In an embodiment, this method employs a compound that inhibits 50% of the enzyme's activity at a concentration of 10 nanomolar or less.

In an embodiment, this method includes exposing said beta-secretase to said compound in vitro.

In an embodiment, this method includes exposing said beta-secretase to said compound in a cell.

In an embodiment, this method includes exposing said beta-secretase to said compound in a cell in an animal.

In an embodiment, this method includes exposing said beta-secretase to said compound in a human.

The invention also includes a method for inhibiting cleavage of amyloid precursor protein (APP), in a reaction mixture, at a site between Met596 and Asp597, numbered for the APP-695 amino acid isotype; or at a corresponding site of an isotype or mutant thereof, including exposing said reaction mixture to an effective inhibitory amount of a compound of formula (AA), (I) or (X), or a pharmaceutically acceptable salt thereof.

In an embodiment, this method employs a cleavage site: between Met652 and Asp653, numbered for the APP-751 isotype; between Met 671 and Asp 672, numbered for the APP-770 isotype; between Leu596 and Asp597 of the APP-695 Swedish Mutation; between Leu652 and Asp653 of the APP-751 Swedish Mutation; or between Leu671 and Asp672 of the APP-770 Swedish Mutation.

In an embodiment, this method exposes said reaction mixture in vitro.

In an embodiment, this method exposes said reaction mixture in a cell.

In an embodiment, this method exposes said reaction mixture in an animal cell.

In an embodiment, this method exposes said reaction mixture in a human cell.

The invention also includes a method for inhibiting production of amyloid beta peptide (A beta) in a cell, including administering to said cell a compound of formula (AA), (I) or (X), under conditions whereby an effective inhibitory amount of a compound of formula (Y), or a pharmaceutically acceptable salt thereof, is formed.

In an embodiment, this method includes administering to an animal.

In an embodiment, this method includes administering to a human.

The invention also includes a method for inhibiting the production of beta-amyloid plaque in an animal, including administering to said animal a compound of formula (AA), (I) or (X), under conditions whereby an effective inhibitory amount of a compound of formula (Y), or a pharmaceutically acceptable salt thereof, is formed.

In an embodiment, this method includes administering to a human.

The invention also includes a method for treating or preventing a disease characterized by beta-amyloid deposits in the brain including administering to a patient an effective therapeutic amount of a compound of formula (AA), (I) or (X), under conditions whereby an effective inhibitory amount of a compound of formula (Y), or a pharmaceutically acceptable salt thereof, is formed.

In an embodiment, this method results in a compound of formula (Y) that inhibits 50% of the enzyme's activity at a concentration of less than 50 micromolar.

In an embodiment, this method results in a compound of formula (Y) that inhibits 50% of the enzyme's activity at a concentration of 10 micromolar or less.

In an embodiment, this method results in a compound of formula (Y) that inhibits 50% of the enzyme's activity at a concentration of 1 micromolar or less.

In an embodiment, this method results in a compound of formula (Y) that inhibits 50% of the enzyme's activity at a concentration of 10 nanomolar or less.

In an embodiment, this method employs a compound at a therapeutic amount in the range of from about 0.1 to about 1500 mg/day.

In an embodiment, this method employs a compound at a therapeutic amount in the range of from about 15 to about 1000 mg/day.

In an embodiment, this method employs a compound at a therapeutic amount in the range of from about 1 to about 100 mg/day.

In an embodiment, this method employs a compound at a therapeutic amount in the range of from about 5 to about 50 mg/day.

In an embodiment, this method can be used where said disease is Alzheimer's disease.

In an embodiment, this method can be used where said disease is Mild Cognitive Impairment, Down's Syndrome, or Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type.

The invention also includes a component kit including component parts capable of being assembled, in which at least one component part includes a compound of formula AA, I or X enclosed in a container.

In an embodiment, this component kit includes lyophilized compound, and at least one further component part includes a diluent.

The invention also includes a container kit including a plurality of containers, each container including one or more unit dose of a compound of formula (AA), (I) or (X):, or a pharmaceutically acceptable salt thereof.

In an embodiment, this container kit includes each container adapted for oral delivery and includes a tablet, gel, or capsule.

In an embodiment, this container kit includes each container adapted for parenteral delivery and includes a depot product, syringe, ampoule, or vial.

In an embodiment, this container kit includes each container adapted for topical delivery and includes a patch, medipad, ointment, or cream.

The invention also includes an agent kit including a compound of formula (AA), (I) or (X), or a pharmaceutically acceptable salt thereof; and one or more therapeutic agent selected from the group consisting of an antioxidant, an anti-inflammatory, a gamma secretase inhibitor, a neurotrophic agent, an acetyl cholinesterase inhibitor, a statin, an A beta peptide, and an anti-A beta antibody.

The invention also includes a composition including a compound of formula (AA), (I) or (X), or a pharmaceutically acceptable salt thereof; and an inert diluent or edible carrier.

In an embodiment, this composition includes a carrier that is an oil.

The invention also includes a composition including: a compound of formula (AA), (I) or (X), or a pharmaceutically acceptable salt thereof; and a binder, excipient, disintegrating agent, lubricant, or gildant.

The invention also includes a composition including a compound of formula (AA), (I) or (X), or a pharmaceutically acceptable salt thereof; disposed in a cream, ointment, or patch.

The invention provides compounds of formula (AA), formula (I) and (X) that can be used to generate compounds of formula (Y), that are useful in treating and preventing Alzheimer's disease. The compounds of the invention can be prepared by one skilled in the art based only on knowledge of the compound's chemical structure. The chemistry for the preparation of the compounds of this invention is known to those skilled in the art. In fact, there is more than one process to prepare the compounds of the invention. Specific examples of methods of preparation can be found in the art. For examples, see J. Org. Chem. 1998, 63, 4898-4906; J. Org. Chem. 1997, 62, 9348-9353; J. Org. Chem. 1996, 61, 5528-5531; J. Med. Chem. 1993, 36, 320-330; J. Am. Chem. Soc. 1999, 121, 1145-1155; and references cited therein. See also U.S. Pat. Nos. 6,150,530, 5,892,052, 5,696,270, and 5,362,912, which are incorporated herein by reference, and references cited therein.

Examples of various processes that can be used to prepare the compounds of the invention are set forth below.

A general process to prepare the compounds of formula I and X is set forth in SCHEME A. The chemistry is straight forward and in summary involves the steps of N-protecting the amino acid (A) starting material to produce the corresponding protected amino acid (II), reaction of the protected amino acid (II) with diazomethane followed by work-up to add a carbon atom to produce the corresponding protected compound (III), reduction of the protected halide to the corresponding alcohol (IV), formation of the corresponding epoxide (V), opening of the epoxide (V) with a C-terminal amine, R_(C)—NH₂ (VI) to produce the corresponding protected alcohol (VII).

Compounds of formula (I) can be prepared by reacting protected alcohol (VII) with an amide forming agent such as, for example, (R_(N)—)₂O or R_(N)—X or R_(N)—OH (IX) to produce alcohol (IA). Alcohol (IA) then has the nitrogen protecting group removed to produce the corresponding compounds of formula (I).

Compounds of formula (X) can be prepared by further N-protecting alcohol (VII) to form the diprotected alcohol (XB). Diprotected alcohol (XB) is reacted with an amide forming agent such as, for example, (R_(N)—)₂O or R_(N)—X or R_(N)—OH (IX) to produce compound (XA). Compound (XA) then has the nitrogen protecting groups removed to produce the corresponding compounds of formula (X).

One skilled in the art will appreciate that these are all known reactions in organic chemistry. A chemist skilled in the art, knowing the chemical structure of the compounds (AA), (I) and (X) of the invention would be able to prepare them by known methods from known starting materials without any additional information. The explanation below therefore is not necessary but is deemed helpful to those skilled in the art who desire to make the compounds of the invention.

The backbone of the intermediate (VII), from which the compounds of formula (AA), (I) and (X) can be readily prepared, can be considered a hydroxyethylamine moiety, —NH—CH(R)—CH(OH)—. Such backbones can be prepared by methods disclosed in the literature and known to those skilled in the art. For example, J. Med. Chem., 36, 288-291 (1993), Tetrahedron Letters, 28, 5569-5572 (1987), J. Med. Chem., 38, 581-584 (1995) and Tetrahedron Letters, 38, 619-620 (1997) and WO 02/02506 all disclose processes to prepare hydroxyethylamine type compounds and/or their intermediates.

SCHEME A sets forth a general method used in the invention to prepare the appropriately substituted amines I and X. The compounds of the invention are prepared by starting with the corresponding amino acid (A). The amino acids (A) are known to those skilled in the art or can be readily prepared by methods known to those skilled in the art. The compounds of the invention have at least two chiral centers, which give 2 sets of diastereomers, each of which is racemic for a total of at least four stereoisomers. While biologically active end products result from all stereoisomers, the (S,R) configuration is preferred. The first of these chiral centers (the carbon carrying R₁) derives from the amino acid starting material (A). It is preferred to commercially obtain or produce the desired enantiomer rather than produce an enantiomerically impure mixture and then have to separate out the desired enantiomer. Thus it is preferred to start the process with enantiomerically pure (S)-amino acid (A) of the same configuration as that of the desired X product.

In Scheme A, the protection of free amine (A) to produce the (S)-protected amino acid (II) is depicted. Amino protecting groups are known to those skilled in the art, as discussed below. See for example, “Protecting Groups in Organic Synthesis”, John Wiley and sons, New York, N.Y., 1981, Chapter 7; “Protecting Groups in Organic Chemistry”, Plenum Press, New York, N.Y., 1973, Chapter 2. The function of the amino protecting group is to protect the free amino functionality (—NH₂) during subsequent reactions on the (S)-amino acid (A) which would not proceed either because the amino group would react and be functionalized in a way that is inconsistent with its need to be free for subsequent reactions or the free amino group would interfere in the reaction. When the amino protecting group is no longer needed, it is removed by methods known to those skilled in the art. By definition the amino protecting group must be readily removable as is known to those skilled in the art by methods known to those skilled in the art. Suitable amino PROTECTING GROUPs are discussed below.

The (S)-protected amino acid (II) is transformed to the corresponding (S)-protected compound (III) by two different methods depending on nature of R₂ and R₃.

R₂ and R₃ can be the same or different. It is preferred that R₂ and R₃ both be —H. If R₂ and R₃ are not the same, an additional chiral or stereogenic center is added to the molecule. To produce compounds of formula (III) where R₂ and R₃ are both —H, the (S)-protected amino acid (II) is reacted with diazomethane, as is known to those skilled in the art, followed by reaction with a compound of the formula H—X₁ to produce the (S)-protected compound (III). X1 includes —Cl, —Br, —I, —O-tosylate, —O-mesylate, —O-nosylate and —O-brosylate. It is preferred that —X₁ be —Br or —Cl. Suitable reaction conditions include running the reaction in inert solvents, such as but not limited to ether, tetrahydrofuran and the like. The reactions from the (S)-protected amino acid (II) to the (S)-protected compound (III) are carried out for a period of time between 10 minutes and 1 day and at temperatures ranging from about −78° to about 20-25°. It is preferred to conduct the reactions for a period of time between 1-4 hours and at temperatures between −30° to −10°. This process adds one methylene group.

Alternatively, the (S)-protected compounds of formula (III) can be prepared by first converting the (S)-protected amino acid (II) to a corresponding methyl or ethyl ester, according to methods established in the art, followed by treatment with a reagent of formula X₁—C(R₂) (R₃)—X₁ and a strong metal base. The base serves to affect a halogen-metal exchange, where the —X₁ undergoing exchange is a halogen selected from chlorine, bromine or iodine. The nucleophilic addition to the ester derivative gives directly the (S)-protected compound (III). Suitable bases include, but are not limited to the alkyllithiums including, for example, sec-butyllithium, n-butyllithium, and t-butyllithium. The reactions are preferably conducted at low temperature, such as −78°. Suitable reaction conditions include running the reaction in inert solvents, such as but not limited to, ether, tetrahydrofuran and the like. Where R₂ and R₃ are both hydrogen, then examples of X₁—C(R₂) (R₃)—X₁ include dibromomethane, diiodomethane, chloroiodomethane, bromoiodomethane and bromochloromethane. One skilled in the art knows the preferred conditions required to conduct this reaction. Furthermore, if R₂ and/or R₃ are not —H, then by the addition of —C(R₂) (R₃)—X₁ to esters of the (S)-protected amino acid (II) to produce the (S)-protected compound (III), an additional chiral center will be incorporated into the product, provided that R₂ and R₃ are not the same.

The (S)-protected compound (III) is then reduced by means known to those skilled in the art for reduction of a ketone to the corresponding secondary alcohol affording the corresponding alcohol (IV). The means and reaction conditions for reducing the (S)-protected compound (III) to the corresponding alcohol (IV) include, for example, sodium borohydride, lithium borohydride, borane, diisobutylaluminum hydride, and lithium aluminium hydride. Sodium borohydride is the preferred reducing agent. The reductions are carried out for a period of time between 1 hour and 3 days at temperatures ranging from −78° to elevated temperature up to the reflux point of the solvent employed. It is preferred to conduct the reduction between −78° and 0°. If borane is used, it may be employed as a complex, for example, borane-methyl sulfide complex, borane-piperidine complex, or borane-tetrahydrofuran complex. The preferred combination of reducing agents and reaction conditions needed are known to those skilled in the art, see for example, Larock, R. C. in Comprehensive Organic Transformations, VCH Publishers, 1989. The reduction of the (S)-protected compound (III) to the corresponding alcohol (IV) produces the second chiral center (third chiral center if R₂ and R₃ are not the same). The reduction of the (S)-protected compound (III) produces a mixture of enantiomers at the second center, (S, R/S)-alcohol (IV). This enantiomeric mixture is then separated by means known to those skilled in the art such as selective low-temperature recrystallization or chromatographic separation, for example by HPLC, employing commercially available chiral columns. The enantiomer that is used in the remainder of the process of SCHEME A is the (S,S)-alcohol (IV) since this enantiomer will give the desired (S,R)-substituted compound I or X.

The (S, S)-alcohol (IV) is transformed to the corresponding epoxide (V) by means known to those skilled in the art. The stereochemistry of the (S)-(IV) center is maintained in forming the epoxide (V). A preferred means is by reaction with base, for example, but not limited to, hydroxide ion generated from sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. Reaction conditions include the use of C₁-C₆ alcohol solvents; ethanol is preferred. A common co-solvent, such as for example, ethyl acetate may also be employed. Reactions are conducted at temperatures ranging from −45° up to the reflux temperature of the alcohol employed; preferred temperature ranges are between −20° and 40°.

An alternative, and preferable process for preparing the epoxide (V) when R₁ is 3,5-difluorobenzyl, is set forth in SCHEME D. The first step of the process is to protect the free amino group of the (S)-amino acid (A) with an amino protecting group, PROTECTING GROUP, as previously discussed to produce the (S)-protected amino acid (II).

In the alternative process, the (S)-protected amino acid (A) is transformed to the corresponding (S)-protected ester (XVII) in one of a number of ways. One method involves the use of lithium hydroxide. Using lithium hydroxide, the (S)-protected amino acid (A) and the lithium hydroxide are mixed and cooled to from about −20° to about 10°. Next a methylating agent, selected from the group consisting of dimethylsulfate, methyl iodide and methyl triflate, is added. It is more preferred that the methylating agent is dimethylsulfate. This is followed by heating to from about 20° to about 50°.

Alternatively, the (S)-protected amino acid (A) is contacted with a weak base such as bicarbonate or preferably carbonate. This is followed by addition of the methylating agent. Heat is not necessary but can be used to facilitate the reaction. The carbonate method is known to those skilled in the art. For those (S)-protected esters (XVII) where Z₁ is not methyl, one skilled in the art knowing the chemical structure would know how to prepare the desired compounds from known starting materials. In one known method the (S)-protected amino acid (A) is contacted with an activating agent, such as DCC, followed by addition of the appropriate alcohol, Z₁—OH. This method is operable when Z₁ is C₁-C₄ alkyl (optionally substituted), —CH₂—CH═CH₂ or phenyl (optionally substituted).

SCHEME E sets forth an alternative process for the preparation of the ester (II). In the process of SCHEME E, the aldehyde (XX), which is known to those skilled in the art, is reacted with the phosphorous compound (XXI), where X₃ is a good leaving group, to produce the olefin (XXII). The phosphorous compounds (XXI) are known to those skilled in the art. It is preferred that X₃ is C₁-C₃ alkyl; it is more preferred that X₃ is C₁ alkyl. The aldehyde (XX) and the phosphate (XXI) are combined in an organic solvent then cooled to about 0°. A base such as DBU or TMG is added and the contents of the reaction mixture are warmed to about 20-25° and stirred until the reaction is complete. Once the reaction is complete, it is preferred to separate the E- and Z-olefin isomers (XXII). The separation is done by methods known to those skilled in the art, such as by silica gel chromatography. Next the olefin (XXII) is hydrogenated with a suitable hydrogenation catalyst to obtain the desired ester (II). Some hydrogenation reactions will give racemic ester (II). The desired stereochemistry of the ester (II) is (S)-, and therefore it is preferable to use the Z-olefin (XXII) with a hydrogenation catalyst. It is preferred that the hydrogenation catalyst is a compound of the formula [Rh(diene)L]⁺X⁻

-   -   where Rh is rhodium;     -   where diene is cyclootediene and nonbornadiene;     -   where L is DIPMAP, MeDuPhos, EtDuPhos, Binaphane, f-Binaphane,         Me-KetalPhos, Me-f-KetalPhos, BINAP, DIOP, BPPFA, BPPM,         CHIRAPHOS, PROPHOS, NORPHOS, CYCLOPHOS, BDPP, DEGPHOS, PNNP and         where X is ClO₄ ⁻, BF₄ ⁻, CF₃—SO₃ ⁻, Cl⁻, Br⁻, PF₆ ⁻ and SbF₆ ⁻.         It is preferred that the hydrogenation catalyst be either DIPMAP         or EtDuPhos. Suitable solvents include polar solvents such as         alcohols, preferably C₁-C₅ alcohols and THF, more preferably         methanol, ethanol, isopropanol and THF. The chiral hydrogenation         is performed in a temperature range of from about −20° to about         reflux. It is preferred that the reaction be performed in the         temperature range from about 0° to about room temperature (25°).         The chiral hydrogenation is performed under a pressure of from         about one atmosphere to about 100 psig; it is more preferred         that the chiral hydrogenation be performed under a pressure of         from about 10 psig to about 40 psig.

The (S)-protected ester (II) is then transformed to the corresponding (S)-protected ketone (III) by reaction with a slight excess of a compound of the formula CH₂ClX² where X² is —Br and —I in one of two different ways. In one process, no exogenous nucleophile is used. That process requires (1) the presence of three or more equivalents of strong base which has a pK_(b) of greater than about 30 followed by (2) adding acid. The other process requires (1) the presence of about 2 to about 2.5 equivalents of strong base which has a pK_(b) of greater than about 30, (2) contacting the mixture of step (1) with about 1 to about 1.5 equivalents of an exogenous nucleophile and (3) adding acid. Suitable strong bases are those which has a pK_(b) of greater than about 30. It is preferred that the strong base be selected from the group consisting of LDA, LiHMDS and KHMDS; it is more preferred that the strong base be LDA. Suitable acids are those, which have a pk_(a) of less than about 10. It is preferred the acid be selected from the group consisting of acetic, sulfuric, hydrochloric, citric, phosphoric and benzoic acids; it is more preferred that the acid be acetic acid. The preferred solvent for the process is THF. The reaction can be performed in the temperature range from about −80° to about −50°; it is preferred to perform the reaction in the temperature range of from about −75° to about −65°. Suitable nucleophiles include alkyl lithium, aryl lithium, alkyl-Grignard and aryl-Grignard reagents. It is preferred that the nucleophile be selected from the group consisting of phenyl lithium, n-butyl lithium, methyl magnesium bromide, methyl magnesium chloride, phenyl magnesium bromide, phenyl magnesium chloride; it is more preferred that the nucleophile be n-butyl lithium.

The (S)-protected ketone (III) is then reduced to the corresponding (S)-alcohol (IV) by means known to those skilled in the art for reduction of a ketone to the corresponding secondary alcohol. The means and reaction conditions for reducing the (S)-protected compound (III) to the corresponding alcohol (IV) include, for example, sodium borohydride, lithium borohydride, borane, diisobutylaluminum hydride, zinc borohydride and lithium aluminium hydride. Sodium borohydride is the preferred reducing agent. The reductions are carried out for a period of time between about 1 hour and about 3 days at temperatures ranging from about −78° to elevated temperature up to the reflux point of the solvent employed. It is preferred to conduct the reduction between about −78° and about 0°. If borane is used, it may be employed as a complex, for example, borane-methyl sulfide complex, borane-piperidine complex, or borane-tetrahydrofuran complex. The preferred combination of reducing agents and reaction conditions needed are known to those skilled in the art, see for example, Larock, R. C. in Comprehensive Organic Transformations, VCH Publishers, 1989. The reduction of the (S)-protected compound (III) to the corresponding alcohol (IV) produces a second chiral center. The reduction of the (S)-protected compound (III) produces a mixture of diastereomers at the second center, (S, R/S)-alcohol (IV). This diastereomeric mixture is then separated by means known to those skilled in the art such as selective low-temperature recrystallization or chromatographic separation, most preferably by recrystallization or by employing commercially available chiral columns. The diastereomer that is used in the remainder of the process of SCHEME A is the (S,S)-alcohol (IV) since this stereochemistry will give the desired epoxide (V).

The alcohol (IV) is transformed to the corresponding epoxide (V) by means known to those skilled in the art. The stereochemistry of the (S)-(IV) center is maintained in forming the epoxide (V). A preferred means is by reaction with base, for example, but not limited to, hydroxide ion generated from sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. Reaction conditions include the use of C₁-C₆ alcohol solvents; ethanol is preferred. A common co-solvent, such as for example, ethyl acetate may also be employed. Reactions are conducted at temperatures ranging from about −45° up to the reflux temperature of the alcohol employed; preferred temperature ranges are between about −20° and about 40°.

The epoxide (V) is then reacted with the appropriately substituted C-terminal amine, R_(C)—NH₂ (VI) by means known to those skilled in the art which opens the epoxide to produce the desired corresponding enantiomerically pure (S,R)-protected alcohol (VII). The substituted C-terminal amines, R_(C)—NH₂ (VI) of this invention are commercially available or are known to those skilled in the art and can be readily prepared from known compounds. It is preferred that when R_(C) is phenyl, it is substituted in the 3-position or 3,5-positions.

Suitable reaction conditions for opening the epoxide (V) include running the reaction in a wide range of common and inert solvents. C₁-C₆ alcohol solvents are preferred and isopropyl alcohol most preferred. The reactions can be run at temperatures ranging from 20-25° up to the reflux temperature of the alcohol employed. The preferred temperature range for conducting the reaction is between 50° up to the reflux temperature of the alcohol employed. When the substituted C-terminal amine (VI) is a 1-amino-3,5-cis-dimethyl cyclohexyldicarboxylate it is preferably prepared as follows. To dimethyl-5-isophthalate in acetic acid and methanol, is added rhodium in alumina in a high-pressure bottle. The bottle is saturated with hydrogen at 55 psi and shaken for one week of time. The mixture is then filtered through a thick layer of celite cake and rinsed with methanol three times, the solvents are removed under reduced pressure (with heat) to give a concentrate. The concentrate is triturated with ether and filtered again to give the desired C-terminal amine (VI). When the substituted C-terminal amine (VI) is 1-amino-3,5-cis-dimethoxy cyclohexane it is preferably following the general procedure above and making non-critical variations but starting with 3,5-dimethoxyaniline.

When the substituted C-terminal amine (VI) is an aminomethyl group where the substituent on the methyl group is an aryl group, for example NH₂—CH₂-aryl, is not commercially available it is preferably prepared as follows. A suitable starting material is the (appropriately substituted) aralkyl compound. The first step is bromination of the alkyl substituent via methods known to those skilled in the art, see for example R. C. Larock in Comprehensive Organic Transformations, VCH Publishers, 1989, p. 313. Next the alkyl halide is reacted with azide to produce the aryl-(alkyl)-azide. Last the azide is reduced to the corresponding amine by hydrogen/catalyst to give the C-terminal amine (VI) of formula NH₂—CH₂—R_(C-aryl).

SCHEME B discloses an alternative process for production of the enantiomerically pure (S,R)-protected alcohol (VII) from the (S)-protected compound (III). In the alternative process, the (S)-protected compound (III) is first reacted with the appropriately substituted C-terminal amine R_(C)—NH₂ (VI) using the preferred conditions described above to produce the corresponding (S)-protected ketone (XI) which is then reduced using the preferred conditions described above to produce the corresponding (S,R)-protected alcohol (VII).

SCHEME C discloses another alternative process for production of enantiomerically pure (S,R)-protected alcohol (VII) but this time from the epoxide (V). In the process of SCHEME C, the epoxide (V) is reacted with azide to produce the corresponding enantiomerically pure (S,R)-protected azide (XII). Conditions to conduct the azide mediated epoxide opening are known to those skilled in the art, see for example, J. March, Advanced Organic Chemistry, 3^(rd) Edition, John Wiley & Sons Publishers, 1985, p. 380. Next, the (S,R)-protected azide (XII) is reduced to the corresponding protected amine (XIII) by methods known to those skilled in the art. Preferred reducing conditions to reduce the (S,R)-protected azide (XII) in the presence of a t-butoxycarbonyl N-protecting group include catalytic hydrogenation, the conditions for which are known to those skilled in the art. Alternative reducing conditions which may be used to avoid N-deprotection with protecting groups other than t-butoxycarbonyl are known to those skilled in the art, see for example, R. C. Larock in Comprehensive Organic Transformations, VCH Publishers, 1989, p. 409. Last, the (S,R)-amine (XIII) is transformed to the corresponding protected alcohol (VII) by nitrogen alkylation with a compound of the formula R_(C)—X₃. X₃ is an appropriate leaving group, such as but not limited to, —Cl, —Br, —I, —O-mesylate, —O-tosylate, O-triflate, etc. X₃ may also be an aldehyde; the corresponding coupling with (XIII) via the known reductive amination procedure gives the protected (S,R)-alcohol (VII).

In the formation of compounds of formula (I), the protected alcohol (VII) is reacted with an appropriately substituted amide forming agent (IX) such as, for example, an anhydride, acyl halide, or acid of the formulas (R_(N))₂O or R_(N)X or R_(N)OH (IX) respectively, by means known to those skilled in the art to produce the corresponding (S,R)-substituted amine (IA). Nitrogen acylation conditions for reaction of the alcohol (VII) with an amide forming agent (IX) to produce the corresponding compound (IA) are known to those skilled in the art and can be found, for example, in R. C. Larock in Comprehensive Organic Transformations, VCH Publishers, 1989, p. 981, 979, and 972. The (S,R)-protected amine (IA) is deprotected to the corresponding compounds (I) by means known to those skilled in the art for removal of amine protecting group. Suitable means for removal of the amine protecting group depend on the nature of the protecting group. Those skilled in the art, knowing the nature of a specific protecting group, know which reagent is preferable for its removal. For example, it is preferred to remove the preferred protecting group, BOC, by dissolving the (S,R)-protected amine (IA) in a trifluoroacetic acid/dichloromethane (1/1) mixture. When complete, the solvents are removed under reduced pressure to give the corresponding (S,R)-amine (I) (as the corresponding salt, i.e. trifluoroacetic acid salt) which is used without further purification. However, if desired, the (S,R)-amine (I) can be purified further by means known to those skilled in the art, such as for example, recrystallization. Further, if the non-salt form is desired that also can be obtained by means known to those skilled in the art, such as for example, preparing the free base amine via treatment of the salt with mild basic conditions. Additional BOC deprotection conditions and deprotection conditions for other protecting groups can be found in T. W. Green and P. G. M. Wuts in “Protective Groups in Organic Chemistry, John Wiley and Sons, 1991, p. 309. Suitable chemically suitable salts include trifluoroacetate, and the anion of mineral acids such as chloride, sulfate, phosphate; preferred is trifluoroacetate.

In the formation of compounds of formula (X), alcohol (VII) is further protected as described above to form the diprotectred compound (XB). Compound (XB) is then reacted with an appropriately substituted amide forming agent (IX) to form compound (XA), as described above for compound (IA). Deprotection of (XA) to compunds (X) is conducted as described for the transformation of compound (IA) to compounds (I).

The protection of amines is conducted, where appropriate, by methods known to those skilled in the art. Amino protecting groups are known to those skilled in the art. See for example, “Protecting Groups in Organic Synthesis”, John Wiley and sons, New York, N.Y., 1981, Chapter 7; “Protecting Groups in Organic Chemistry”, Plenum Press, New York, N.Y., 1973, Chapter 2. When the amino protecting group is no longer needed, it is removed by methods known to those skilled in the art. By definition the amino protecting group must be readily removable. A variety of suitable methodologies are known to those skilled in the art; see also T. W. Green and P. G. M. Wuts in “Protective Groups in Organic Chemistry, John Wiley and Sons, 1991. Suitable amino protecting groups include t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycabonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl, isobrornyloxycarbonyl, 1-piperidyloxycarbonyl, 9-fluoroenylmethyl carbonate, —CH—CH═CH₂ and phenyl-C(═N—)—H.

It is preferred that the protecting group be t-butoxycarbonyl (BOC) and/or benzyloxycarbonyl (CBZ), it is more preferred that the protecting group be t-butoxycarbonyl. One skilled in the art will recognize suitable methods of introducing a t-butoxycarbonyl or benzyloxycarbonyl protecting group and may additionally consult T. W. Green and P. G. M. Wuts in “Protective Groups in Organic Chemistry, John Wiley and Sons, 1991 for guidance.

The compounds of the invention may contain geometric or optical isomers as well as tautomers. Thus, the invention includes all tautomers and pure geometric isomers, such as the E and Z geometric isomers, as well as mixtures thereof. Further, the invention includes pure enantiomers and diastereomers as well as mixtures thereof, including racemic mixtures. The individual geometric isomers, enantiomers or diastereomers may be prepared or isolated by methods known to those skilled in the art, including but not limited to chiral chromatography; preparing diastereomers, separating the diastereomers and converting the diastereomers into enantiomers through the use of a chiral resolving agent.

Compounds of the invention with designated stereochemistry can be included in mixtures, including racemic mixtures, with other enantiomers, diastereomers, geometric isomers or tautomers. In a preferred aspect, compounds of the invention with (S, R, R), (S, S, S), or (S, R, S) stereochemistry are typically present in these mixtures in excess of 50 percent. Preferably, compounds of the invention with designated stereochemistry are present in these mixtures in excess of 80 percent. More preferably, compounds of the invention with designated stereochemistry are present in these mixtures in excess of 90 percent. Even more preferably, compounds of the invention with designated stereochemistry are present in these mixtures in excess of 99 percent.

The invention encompasses pharmaceutically acceptable salts of the compounds of formula (AA), (I) and (X). Pharmaceutically acceptable salts are preferred over the corresponding amines of formula (AA), (I) or (X) since they produce compounds which are more water soluble, stable and/or more crystalline. Pharmaceutically acceptable salts are any salt which retains the activity of the parent compound and does not impart any deleterious or undesirable effect on the subject to whom it is administered and in the context in which it is administered. Pharmaceutically acceptable salts include salts of both inorganic and organic acids. The preferred pharmaceutically acceptable salts include salts of the following acids acetic, aspartic, benzenesulfonic, benzoic, bicarbonic, bisulfuric, bitartaric, butyric, calcium edetate, camsylic, carbonic, chlorobenzoic, citric, edetic, edisylic, estolic, esyl, esylic, formic, fumaric, gluceptic, gluconic, glutamic, glycollylarsanilic, hexamic, hexylresorcinoic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, maleic, malic, malonic, mandelic, methanesulfonic, methylnitric, methylsulfuric, mucic, muconic, napsylic, nitric, oxalic, p-nitromethanesulfonic, pamoic, pantothenic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, phthalic, polygalactouronic, propionic, salicylic, stearic, succinic, succinic, sulfamic, sulfanilic, sulfonic, sulfuric, tannic, tartaric, teoclic and toluenesulfonic. For other acceptable salts, see Int. J. Pharm., 33, 201-217 (1986) and J. Pharm. Sci., 66(1), 1, (1977).

The invention provides compounds, compositions, kits, and methods for inhibiting beta-secretase enzyme activity and A beta peptide production. Inhibition of beta-secretase enzyme activity halts or reduces the production of A beta from APP and reduces or eliminates the formation of beta-amyloid deposits in the brain.

Methods of the Invention

The compounds of the invention, and pharmaceutically acceptable salts thereof, are useful for treating humans or animals suffering from a condition characterized by a pathological form of beta-amyloid peptide, such as beta-amyloid plaques, and for helping to prevent or delay the onset of such a condition.

As used herein, the term “treating” means that the compounds of the invention can be used in humans with at least a tentative diagnosis of disease. The compounds of the invention will delay or slow the progression of the disease thereby giving the individual a more useful life span.

The term “preventing” means that the compounds of the invention are useful when administered to a patient who has not been diagnosed as possibly having the disease at the time of administration, but who would normally be expected to develop the disease or be at increased risk for the disease. The compounds of the invention will slow the development of disease symptoms, delay the onset of the disease, or prevent the individual from developing the disease at all. Preventing also includes administration of the compounds of the invention to those individuals thought to be predisposed to the disease due to age, familial history, genetic or chromosomal abnormalities, and/or due to the presence of one or more biological markers for the disease, such as a known genetic mutation of APP or APP cleavage products in brain tissues or fluids.

In treating or preventing the above diseases, the compounds of the invention are administered in a therapeutically effective amount. The therapeutically effective amount will vary depending on the particular compound used and the route of administration, as is known to those skilled in the art.

In treating a patient displaying any of the diagnosed above conditions a physician may administer a compound of the invention immediately and continue administration indefinitely, as needed. In treating patients who are not diagnosed as having Alzheimer's disease, but who are believed to be at substantial risk for Alzheimer's disease, the physician should preferably start treatment when the patient first experiences early pre-Alzheimer's symptoms such as, memory or cognitive problems associated with aging. In addition, there are some patients who may be determined to be at risk for developing Alzheimer's through the detection of a genetic marker such as APOE4 or other biological indicators that are predictive for Alzheimer's disease. In these situations, even though the patient does not have symptoms of the disease, administration of the compounds of the invention may be started before symptoms appear, and treatment may be continued indefinitely to prevent or delay the onset of the disease.

Dosage Forms and Amounts

The compounds of the invention can be administered orally, parenterally, (IV, IM, depo-IM, SQ, and depo SQ), sublingually, intranasally (inhalation), intrathecally, topically, or rectally. Dosage forms known to those of skill in the art are suitable for delivery of the compounds of the invention.

Compositions are provided that contain therapeutically effective amounts of the compounds of the invention. The compounds are preferably formulated into suitable pharmaceutical preparations such as tablets, capsules, or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration. Typically the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art.

About 1 to 500 mg of a compound or mixture of compounds of the invention or a physiologically acceptable salt or ester is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in those compositions or preparations is such that a suitable dosage in the range indicated is obtained. The compositions are preferably formulated in a unit dosage form, each dosage containing from about 2 to about 100 mg, more preferably about 10 to about 30 mg of the active ingredient. The term “unit dosage from” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

To prepare compositions, one or more compounds of the invention are mixed with a suitable pharmaceutically acceptable carrier. Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion, or the like. Liposomal suspensions may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for lessening or ameliorating at least one symptom of the disease, disorder, or condition treated and may be empirically determined.

Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration. In addition, the active materials can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, or have another action. The compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients.

Where the compounds exhibit insufficient solubility, methods for solubilizing may be used. Such methods are known and include, but are not limited to, using cosolvents such as dimethylsulfoxide (DMSO), using surfactants such as Tween®, and dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as salts or prodrugs may also be used in formulating effective pharmaceutical compositions.

The concentration of the compound is effective for delivery of an amount upon administration that lessens or ameliorates at least one symptom of the disorder for which the compound is administered. Typically, the compositions are formulated for single dosage administration.

The compounds of the invention may be prepared with carriers that protect them against rapid elimination from the body, such as time-release formulations or coatings. Such carriers include controlled release formulations, such as, but not limited to, microencapsulated delivery systems. The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated. The therapeutically effective concentration may be determined empirically by testing the compounds in known in vitro and in vivo model systems for the treated disorder.

The compounds and compositions of the invention can be enclosed in multiple or single dose containers. The enclosed compounds and compositions can be provided in kits, for example, including component parts that can be assembled for use. For example, a compound inhibitor in lyophilized form and a suitable diluent may be provided as separated components for combination prior to use. A kit may include a compound inhibitor and a second therapeutic agent for co-administration. The inhibitor and second therapeutic agent may be provided as separate component parts. A kit may include a plurality of containers, each container holding one or more unit dose of the compound of the invention. The containers are preferably adapted for the desired mode of administration, including, but not limited to tablets, gel capsules, sustained-release capsules, and the like for oral administration; depot products, pre-filled syringes, ampoules, vials, and the like for parenteral administration; and patches, medipads, creams, and the like for topical administration.

The concentration of active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the active compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art.

The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

If oral administration is desired, the compound should be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient.

Oral compositions will generally include an inert diluent or an edible carrier and may be compressed into tablets or enclosed in gelatin capsules. For the purpose of oral therapeutic administration, the active compound or compounds can be incorporated with excipients and used in the form of tablets, capsules, or troches. Pharmaceutically compatible binding agents and adjuvant materials can be included as part of the composition.

The tablets, pills, capsules, troches, and the like can contain any of the following ingredients or compounds of a similar nature: a binder such as, but not limited to, gum tragacanth, acacia, corn starch, or gelatin; an excipient such as microcrystalline cellulose, starch, or lactose; a disintegrating agent such as, but not limited to, alginic acid and corn starch; a lubricant such as, but not limited to, magnesium stearate; a gildant, such as, but not limited to, colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; and a flavoring agent such as peppermint, methyl salicylate, or fruit flavoring.

When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials, which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings, and flavors.

The active materials can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action.

Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent such as water for injection, saline solution, fixed oil, a naturally occurring vegetable oil such as sesame oil, coconut oil, peanut oil, cottonseed oil, and the like, or a synthetic fatty vehicle such as ethyl oleate, and the like, polyethylene glycol, glycerine, propylene glycol, or other synthetic solvent; antimicrobial agents such as benzyl alcohol and methyl parabens; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates, and phosphates; and agents for the adjustment of tonicity such as sodium chloride and dextrose. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass, plastic, or other suitable material. Buffers, preservatives, antioxidants, and the like can be incorporated as required.

Where administered intravenously, suitable carriers include physiological saline, phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents such as glucose, polyethylene glycol, polypropyleneglycol, and mixtures thereof. Liposomal suspensions including tissue-targeted liposomes may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known for example, as described in U.S. Pat. No. 4,522,811.

The active compounds may be prepared with carriers that protect the compound against rapid elimination from the body, such as time-release formulations or coatings. Such carriers include controlled release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid, and the like. Methods for preparation of such formulations are known to those skilled in the art.

The compounds of the invention can be administered orally, parenterally (IV, IM, depo-IM, SQ, and depo-SQ), sublingually, intranasally (inhalation), intrathecally, topically, or rectally. Dosage forms known to those skilled in the art are suitable for delivery of the compounds of the invention.

Compounds of the invention may be administered enterally or parenterally. When administered orally, compounds of the invention can be administered in usual dosage forms for oral administration as is well known to those skilled in the art. These dosage forms include the usual solid unit dosage forms of tablets and capsules as well as liquid dosage forms such as solutions, suspensions, and elixirs. When the solid dosage forms are used, it is preferred that they be of the sustained release type so that the compounds of the invention need to be administered only once or twice daily.

The oral dosage forms are administered to the patient 1, 2, 3, or 4 times daily. It is preferred that the compounds of the invention be administered either three or fewer times, more preferably once or twice daily. Hence, it is preferred that the compounds of the invention be administered in oral dosage form. It is preferred that whatever oral dosage form is used, that it be designed so as to protect the compounds of the invention from the acidic environment of the stomach. Enteric coated tablets are well known to those skilled in the art. In addition, capsules filled with small spheres each coated to protect from the acidic stomach, are also well known to those skilled in the art.

When administered orally, an administered amount therapeutically effective to inhibit beta-secretase activity, to inhibit A beta production, to inhibit A beta deposition, or to treat or prevent AD is from about 0.1 mg/day to about 1,000 mg/day. It is preferred that the oral dosage is from about 1 mg/day to about 100 mg/day. It is more preferred that the oral dosage is from about 5 mg/day to about 50 mg/day. It is understood that while a patient may be started at one dose, that dose may be varied over time as the patient's condition changes.

Compounds of the invention may also be advantageously delivered in a nano crystal dispersion formulation. Preparation of such formulations is described, for example, in U.S. Pat. No. 5,145,684. Nano crystalline dispersions of HIV protease inhibitors and their method of use are described in U.S. Pat. No. 6,045,829. The nano crystalline formulations typically afford greater bioavailability of drug compounds.

The compounds of the invention can be administered parenterally, for example, by IV, IM, depo-IM, SC, or depo-SC. When administered parenterally, a therapeutically effective amount of about 0.5 to about 100 mg/day, preferably from about 5 to about 50 mg daily should be delivered. When a depot formulation is used for injection once a month or once every two weeks, the dose should be about 0.5 mg/day to about 50 mg/day, or a monthly dose of from about 15 mg to about 1,500 mg. In part because of the forgetfulness of the patients with Alzheimer's disease, it is preferred that the parenteral dosage form be a depo formulation.

The compounds of the invention can be administered sublingually. When given sublingually, the compounds of the invention should be given one to four times daily in the amounts described above for IM administration.

The compounds of the invention can be administered intranasally. When given by this route, the appropriate dosage forms are a nasal spray or dry powder, as is known to those skilled in the art. The dosage of the compounds of the invention for intranasal administration is the amount described above for IM administration.

The compounds of the invention can be administered intrathecally. When given by this route the appropriate dosage form can be a parenteral dosage form as is known to those skilled in the art. The dosage of the compounds of the invention for intrathecal administration is the amount described above for IM administration.

The compounds of the invention can be administered topically. When given by this route, the appropriate dosage form is a cream, ointment, or patch. Because of the amount of the compounds of the invention to be administered, the patch is preferred. When administered topically, the dosage is from about 0.5 mg/day to about 200 mg/day. Because the amount that can be delivered by a patch is limited, two or more patches may be used. The number and size of the patch is not important, what is important is that a therapeutically effective amount of the compounds of the invention be delivered as is known to those skilled in the art. The compounds of the invention can be administered rectally by suppository as is known to those skilled in the art. When administered by suppository, the therapeutically effective amount is from about 0.5 mg to about 500 mg.

The compounds of the invention can be administered by implants as is known to those skilled in the art. When administering a compound of the invention by implant, the therapeutically effective amount is the amount described above for depot administration.

Given a particular compound of the invention and a desired dosage form, one skilled in the art would know how to prepare and administer the appropriate dosage form.

The compounds of the invention are used in the same manner, by the same routes of administration, using the same pharmaceutical dosage forms, and at the same dosing schedule as described above, for preventing disease or treating patients with MCI (mild cognitive impairment) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating or preventing Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, and diffuse Lewy body type of Alzheimer's disease.

The compounds of the invention can be used in combination, with each other or with other therapeutic agents or approaches used to treat or prevent the conditions listed above. Such agents or approaches include: acetylcholine esterase inhibitors such as tacrine (tetrahydroaminoacridine, marketed as COGNEX®), donepezil hydrochloride, (marketed as Aricept® and rivastigmine (marketed as Exelon®); gamma-secretase inhibitors; anti-inflammatory agents such as cyclooxygenase II inhibitors; anti-oxidants such as Vitamin E and ginkolides; immunological approaches, such as, for example, immunization with A beta peptide or administration of anti-A beta peptide antibodies; statins; and direct or indirect neurotropic agents such as Cerebrolysin®, AIT-082 (Emilieu, 2000, Arch. Neurol. 57:454), and other neurotropic agents of the future.

In addition, the compounds of formula (AA), (I) or (X) can also be used with inhibitors of P-glycoprotein (P-gp). P-gp inhibitors and the use of such compounds are known to those skilled in the art. See for example, Cancer Research, 53, 4595-4602 (1993), Clin. Cancer Res., 2, 7-12 (1996), Cancer Research, 56, 4171-4179 (1996), International Publications WO99/64001 and WO01/10387. The important thing is that the blood level of the P-gp inhibitor be such that it exerts its effect in inhibiting P-gp from decreasing brain blood levels of the compounds of formula (A). To that end the P-gp inhibitor and the compounds of formula (A) can be administered at the same time, by the same or different route of administration, or at different times. The important thing is not the time of administration but having an effective blood level of the P-gp inhibitor.

Suitable P-gp inhibitors include cyclosporin A, verapamil, tamoxifen, quinidine, Vitamin E-TGPS, ritonavir, megestrol acetate, progesterone, rapamycin, 10,11-methanodibenzosuberane, phenothiazines, acridine derivatives such as GF120918, FK506, VX-710, LY335979, PSC-833, GF-102,918 and other steroids. It is to be understood that additional agents will be found that have the same function and therefore achieve the same outcome; such compounds are also considered to be useful.

The P-gp inhibitors can be administered orally, parenterally, (IV, IM, IM-depo, SQ, SQ-depo), topically, sublingually, rectally, intranasally, intrathecally and by implant.

The therapeutically effective amount of the P-gp inhibitors is from about 0.1 to about 300 mg/kg/day, preferably about 0.1 to about 150 mg/kg daily. It is understood that while a patient may be started on one dose, that dose may have to be varied over time as the patient's condition changes.

When administered orally, the P-gp inhibitors can be administered in usual dosage forms for oral administration as is known to those skilled in the art. These dosage forms include the usual solid unit dosage forms of tablets and capsules as well as liquid dosage forms such as solutions, suspensions and elixirs. When the solid dosage forms are used, it is preferred that they be of the sustained release type so that the P-gp inhibitors need to be administered only once or twice daily. The oral dosage forms are administered to the patient one thru four times daily. It is preferred that the P-gp inhibitors be administered either three or fewer times a day, more preferably once or twice daily. Hence, it is preferred that the P-gp inhibitors be administered in solid dosage form and further it is preferred that the solid dosage form be a sustained release form which permits once or twice daily dosing. It is preferred that what ever dosage form is used, that it be designed so as to protect the P-gp inhibitors from the acidic environment of the stomach. Enteric coated tablets are well known to those skilled in the art. In addition, capsules filled with small spheres each coated to protect from the acidic stomach, are also well known to those skilled in the art.

In addition, the P-gp inhibitors can be administered parenterally. When administered parenterally they can be administered IV, IM, depo-IM, SQ or depo-SQ.

The P-gp inhibitors can be given sublingually. When given sublingually, the P-gp inhibitors should be given one thru four times daily in the same amount as for IM administration.

The P-gp inhibitors can be given intranasally. When given by this route of administration, the appropriate dosage forms are a nasal spray or dry powder as is known to those skilled in the art. The dosage of the P-gp inhibitors for intranasal administration is the same as for IM administration.

The P-gp inhibitors can be given intrathecally. When given by this route of administration the appropriate dosage form can be a parenteral dosage form as is known to those skilled in the art.

The P-gp inhibitors can be given topically. When given by this route of administration, the appropriate dosage form is a cream, ointment or patch. Because of the amount of the P-gp inhibitors needed to be administered the patch is preferred. However, the amount that can be delivered by a patch is limited. Therefore, two or more patches may be required. The number and size of the patch is not important, what is important is that a therapeutically effective amount of the P-gp inhibitors be delivered as is known to those skilled in the art.

The P-gp inhibitors can be administered rectally by suppository as is known to those skilled in the art.

The P-gp inhibitors can be administered by implants as is known to those skilled in the art.

There is nothing novel about the route of administration nor the dosage forms for administering the P-gp inhibitors. Given a particular P-gp inhibitor, and a desired dosage form, one skilled in the art would know how to prepare the appropriate dosage form for the P-gp inhibitor.

It should be apparent to one skilled in the art that the exact dosage and frequency of administration will depend on the particular compounds of the invention administered, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, and other medication the individual may be taking as is well known to administering physicians who are skilled in this art.

Inhibition of APP Cleavage

The compounds of the invention inhibit cleavage of APP between Met595 and Asp596 numbered for the APP695 isoform, or a mutant thereof, or at a corresponding site of a different isoform, such as APP751 or APP770, or a mutant thereof (sometimes referred to as the “beta secretase site”). While not wishing to be bound by a particular theory, inhibition of beta-secretase activity is thought to inhibit production of beta amyloid peptide (A beta). Inhibitory activity is demonstrated in one of a variety of inhibition assays, whereby cleavage of an APP substrate in the presence of a beta-secretase enzyme is analyzed in the presence of the inhibitory compound, under conditions normally sufficient to result in cleavage at the beta-secretase cleavage site. Reduction of APP cleavage at the beta-secretase cleavage site compared with an untreated or inactive control is correlated with inhibitory activity. Assay systems that can be used to demonstrate efficacy of the compound inhibitors of the invention are known. Representative assay systems are described, for example, in U.S. Pat. Nos. 5,942,400, 5,744,346, as well as in the Examples below.

The enzymatic activity of beta-secretase and the production of A beta can be analyzed in vitro or in vivo, using natural, mutated, and/or synthetic APP substrates, natural, mutated, and/or synthetic enzyme, and the test compound. The analysis may involve primary or secondary cells expressing native, mutant, and/or synthetic APP and enzyme, animal models expressing native APP and enzyme, or may utilize transgenic animal models expressing the substrate and enzyme. Detection of enzymatic activity can be by analysis of one or more of the cleavage products, for example, by immunoassay, fluorometric or chromogenic assay, HPLC, or other means of detection. Inhibitory compounds are determined as those having the ability to decrease the amount of beta-secretase cleavage product produced in comparison to a control, where beta-secretase mediated cleavage in the reaction system is observed and measured in the absence of inhibitory compounds.

Beta-Secretase

Various forms of beta-secretase enzyme are known, and are available and useful for assay of enzyme activity and inhibition of enzyme activity. These include native, recombinant, and synthetic forms of the enzyme. Human beta-secretase is known as Beta Site APP Cleaving Enzyme (BACE), Asp2, and memapsin 2, and has been characterized, for example, in U.S. Pat. No. 5,744,346 and published PCT patent applications WO98/22597, WO00/03819, WO01/23533, and WO00/17369, as well as in literature publications (Hussain et al., 1999, Mol. Cell. Neurosci. 14:419-427; Vassar et al., 1999, Science 286:735-741; Yan et al., 1999, Nature 402:533-537; Sinha et al., 1999, Nature 40:537-540; and Lin et al., 2000, PNAS USA 97:1456-1460). Synthetic forms of the enzyme have also been described (WO98/22597 and WO00/17369). Beta-secretase can be extracted and purified from human brain tissue and can be produced in cells, for example mammalian cells expressing recombinant enzyme.

Preferred rearranged compounds are effective to inhibit about 50% of beta-secretase enzymatic activity at a concentration of less than 50 micromolar, preferably at a concentration of 10 micromolar or less, more preferably 1 micromolar or less, and most preferably 10 nanomolar or less.

APP Substrate

Assays that demonstrate inhibition of beta-secretase-mediated cleavage of APP can utilize any of the known forms of APP, including the 695 amino acid “normal” isotype described by Kang et al., 1987, Nature 325:733-6, the 770 amino acid isotype described by Kitaguchi et. al., 1981, Nature 331:530-532, and variants such as the Swedish Mutation (KM670-1NL) (APP-SW), the London Mutation (V7176F), and others. See, for example, U.S. Pat. No. 5,766,846 and also Hardy, 1992, Nature Genet. 1:233-234, for a review of known variant mutations. Additional useful substrates include the dibasic amino acid modification, APP-KK disclosed, for example, in WO 00/17369, fragments of APP, and synthetic peptides containing the beta-secretase cleavage site, wild type (WT) or mutated form, e.g., SW, as described, for example, in U.S. Pat. No. 5,942,400 and WO00/03819.

The APP substrate contains the beta-secretase cleavage site of APP (KM-DA or NL-DA) for example, a complete APP peptide or variant, an APP fragment, a recombinant or synthetic APP, or a fusion peptide. Preferably, the fusion peptide includes the beta-secretase cleavage site fused to a peptide having a moiety useful for enzymatic assay, for example, having isolation and/or detection properties. A useful moiety may be an antigenic epitope for antibody binding, a label or other detection moiety, a binding substrate, and the like.

Antibodies

Products characteristic of APP cleavage can be measured by immunoassay using various antibodies, as described, for example, in Pirttila et al., 1999, Neuro. Lett. 249:21-4, and in U.S. Pat. No. 5,612,486. Useful antibodies to detect A beta include, for example, the monoclonal antibody 6E10 (Senetek, St. Louis, Mo.) that specifically recognizes an epitope on amino acids 1-16 of the A beta peptide; antibodies 162 and 164 (New York State Institute for Basic Research, Staten Island, N.Y.) that are specific for human A beta 1-40 and 1-42, respectively; and antibodies that recognize the junction region of beta-amyloid peptide, the site between residues 16 and 17, as described in U.S. Pat. No. 5,593,846. Antibodies raised against a synthetic peptide of residues 591 to 596 of APP and SW192 antibody raised against 590-596 of the Swedish mutation are also useful in immunoassay of APP and its cleavage products, as described in U.S. Pat. Nos. 5,604,102 and 5,721,130.

Assay Systems

Assays for determining APP cleavage at the beta-secretase cleavage site are well known in the art. Exemplary assays, are described, for example, in U.S. Pat. Nos. 5,744,346 and 5,942,400, and described in the Examples below.

Cell Free Assays

Exemplary assays that can be used to demonstrate the inhibitory activity of the compounds of the invention are described, for example, in WO00/17369, WO 00/03819, and U.S. Pat. No. 5,942,400 and 5,744,346. Such assays can be performed in cell-free incubations or in cellular incubations using cells expressing a beta-secretase and an APP substrate having a beta-secretase cleavage site.

An APP substrate containing the beta-secretase cleavage site of APP, for example, a complete APP or variant, an APP fragment, or a recombinant or synthetic APP substrate containing the amino acid sequence: KM-DA or NL-DA, is incubated in the presence of beta-secretase enzyme, a fragment thereof, or a synthetic or recombinant polypeptide variant having beta-secretase activity and effective to cleave the beta-secretase cleavage site of APP, under incubation conditions suitable for the cleavage activity of the enzyme. Suitable substrates optionally include derivatives that may be fusion proteins or peptides that contain the substrate peptide and a modification useful to facilitate the purification or detection of the peptide or its beta-secretase cleavage products. Useful modifications include the insertion of a known antigenic epitope for antibody binding; the linking of a label or detectable moiety, the linking of a binding substrate, and the like.

Suitable incubation conditions for a cell-free in vitro assay include, for example: approximately 200 nanomolar to 10 micromolar substrate, approximately 10 to 200 picomolar enzyme, and approximately 0.1 nanomolar to 10 micromolar inhibitor compound, in aqueous solution, at an approximate pH of 4-7, at approximately 37 degrees C., for a time period of approximately 10 minutes to 3 hours. These incubation conditions are exemplary only, and can be varied as required for the particular assay components and/or desired measurement system. Optimization of the incubation conditions for the particular assay components should account for the specific beta-secretase enzyme used and its pH optimum, any additional enzymes and/or markers that might be used in the assay, and the like. Such optimization is routine and will not require undue experimentation.

One useful assay utilizes a fusion peptide having maltose binding protein (MBP) fused to the C-terminal 125 amino acids of APP-SW. The MBP portion is captured on an assay substrate by anti-MBP capture antibody. Incubation of the captured fusion protein in the presence of beta-secretase results in cleavage of the substrate at the beta-secretase cleavage site. Analysis of the cleavage activity can be, for example, by immunoassay of cleavage products. One such immunoassay detects a unique epitope exposed at the carboxy terminus of the cleaved fusion protein, for example, using the antibody SW192. This assay is described, for example, in U.S. Pat. No. 5,942,400.

Cellular Assay

Numerous cell-based assays can be used to analyze beta-secretase activity and/or processing of APP to release A beta. Contact of an APP substrate with a beta-secretase enzyme within the cell and in the presence or absence of a compound inhibitor of the invention can be used to demonstrate beta-secretase inhibitory activity of the compound. Preferably, assay in the presence of a useful inhibitory compound provides at least about 30%, most preferably at least about 50% inhibition of the enzymatic activity, as compared with a non-inhibited control.

In one embodiment, cells that naturally express beta-secretase are used. Alternatively, cells are modified to express a recombinant beta-secretase or synthetic variant enzyme as discussed above. The APP substrate may be added to the culture medium and is preferably expressed in the cells. Cells that naturally express APP, variant or mutant forms of APP, or cells transformed to express an isoform of APP, mutant or variant APP, recombinant or synthetic APP, APP fragment, or synthetic APP peptide or fusion protein containing the beta-secretase APP cleavage site can be used, provided that the expressed APP is permitted to contact the enzyme and enzymatic cleavage activity can be analyzed.

Human cell lines that normally process A beta from APP provide a useful means to assay inhibitory activities of the compounds of the invention. Production and release of A beta and/or other cleavage products into the culture medium can be measured, for example by immunoassay, such as Western blot or enzyme-linked immunoassay (EIA) such as by ELISA.

Cells expressing an APP substrate and an active beta-secretase can be incubated in the presence of a compound inhibitor to demonstrate inhibition of enzymatic activity as compared with a control. Activity of beta-secretase can be measured by analysis of one or more cleavage products of the APP substrate. For example, inhibition of beta-secretase activity against the substrate APP would be expected to decrease release of specific beta-secretase induced APP cleavage products such as A beta.

Although both neural and non-neural cells process and release A beta, levels of endogenous beta-secretase activity are low and often difficult to detect by EIA. The use of cell types known to have enhanced beta-secretase activity, enhanced processing of APP to A beta, and/or enhanced production of A beta are therefore preferred. For example, transfection of cells with the Swedish Mutant form of APP (APP-SW); with APP-KK; or with APP-SW-KK provides cells having enhanced beta-secretase activity and producing amounts of A beta that can be readily measured.

In such assays, for example, the cells expressing APP and beta-secretase are incubated in a culture medium under conditions suitable for beta-secretase enzymatic activity at its cleavage site on the APP substrate. On exposure of the cells to the compound inhibitor, the amount of A beta released into the medium and/or the amount of CTF99 fragments of APP in the cell lysates is reduced as compared with the control. The cleavage products of APP can be analyzed, for example, by immune reactions with specific antibodies, as discussed above.

Preferred cells for analysis of beta-secretase activity include primary human neuronal cells, primary transgenic animal neuronal cells where the transgene is APP, and other cells such as those of a stable 293 cell line expressing APP, for example, APP-SW.

In Vivo Assays: Animal Models

Various animal models can be used to analyze beta-secretase activity and/or processing of APP to release A beta, as described above. For example, transgenic animals expressing APP substrate and beta-secretase enzyme can be used to demonstrate inhibitory activity of the compounds of the invention. Certain transgenic animal models have been described, for example, in U.S. Pat. Nos. 5,877,399; 5,612,486; 5,387,742; 5,720,936; 5,850,003; 5,877,015, and 5,811,633, and in Ganes et al., 1995, Nature 373:523. Preferred are animals that exhibit characteristics associated with the pathophysiology of AD. Administration of the compound inhibitors of the invention to the transgenic mice described herein provides an alternative method for demonstrating the inhibitory activity of the compounds. Administration of the compounds in a pharmaceutically effective carrier and via an administrative route that reaches the target tissue in an appropriate therapeutic amount is also preferred.

Inhibition of beta-secretase mediated cleavage of APP at the beta-secretase cleavage site and of A beta release can be analyzed in these animals by measure of cleavage fragments in the animal's body fluids such as cerebral fluid or tissues. Analysis of brain tissues for A beta deposits or plaques is preferred.

On contacting an APP substrate with a beta-secretase enzyme in the presence of an inhibitory compound of the invention and under conditions sufficient to permit enzymatic mediated cleavage of APP and/or release of A beta from the substrate, the compounds of the invention are effective to reduce beta-secretase-mediated cleavage of APP at the beta-secretase cleavage site and/or effective to reduce released amounts of A beta. Where such contacting is the administration of the inhibitory compounds of the invention to an animal model, for example, as described above, the compounds are effective to reduce A beta deposition in brain tissues of the animal, and to reduce the number and/or size of beta amyloid plaques. Where such administration is to a human subject, the compounds are effective to inhibit or slow the progression of disease characterized by enhanced amounts of A beta, to slow the progression of AD in the, and/or to prevent onset or development of AD in a patient at risk for the disease.

Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are hereby incorporated by reference for all purposes.

Definitions

The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.

It should be noted that, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing “a compound” includes a mixture of two or more compounds. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.

The symbol “—” in general represents a bond between two atoms in the chain. Thus CH₃—O—CH₂—CH(R_(i))—CH₃ represents a 2-substituted-1-methoxypropane compound. In addition, the symbol “—” represents the point of attachment of the substituent to a compound. Thus for example aryl(C₁-C₆)alkyl- indicates an alkylaryl group, such as benzyl, attached to the compound at the alkyl moiety.

Where multiple substituents are indicated as being attached to a structure, it is to be understood that the substituents can be the same or different. Thus for example “R_(m) optionally substituted with 1, 2 or 3 R_(q) groups” indicates that R_(m) is substituted with 1, 2, or 3 R_(q) groups where the R_(q) groups can be the same or different.

APP, amyloid precursor protein, is defined as any APP polypeptide, including APP variants, mutations, and isoforms, for example, as disclosed in U.S. Pat. No. 5,766,846.

A beta, amyloid beta peptide, is defined as any peptide resulting from beta-secretase mediated cleavage of APP, including peptides of 39, 40, 41, 42, and 43 amino acids, and extending from the beta-secretase cleavage site to amino acids 39, 40, 41, 42, or 43.

Beta-secretase (BACE1, Asp2, Memapsin 2) is an aspartyl protease that mediates cleavage of APP at the amino-terminal edge of A beta. Human beta-secretase is described, for example, in WO00/17369.

Pharmaceutically acceptable refers to those properties and/or substances that are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability and patient acceptance.

A therapeutically effective amount is defined as an amount effective to reduce or lessen at least one symptom of the disease being treated or to reduce or delay onset of one or more clinical markers or symptoms of the disease.

By “alkyl” and “C₁-C₆ alkyl” in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. It is understood that in cases where an alkyl chain of a substituent (e.g. of an alkyl, alkoxy or alkenyl group) is shorter or longer than 6 carbons, it will be so indicated in the second “C” as, for example, “C₁-C₁₀” indicates a maximum of 10 carbons.

By “alkoxy” and “C₁-C₆ alkoxy” in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, attached through at least one divalent oxygen atom, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexoxy, and 3-methylpentoxy.

By the term “halogen” in the present invention is meant fluorine, bromine, chlorine, and iodine.

“Alkenyl” and “C₂-C₆ alkenyl” means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and from one to three double bonds and includes, for example, ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like.

“Alkynyl” and “C₂-C₆ alkynyl” means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one or two triple bonds and includes ethynyl, propynyl, butynyl, pentyn-2-yl and the like.

As used herein, the term “cycloalkyl” refers to saturated carbocyclic radicals having three to twelve carbon atoms. The cycloalkyl can be monocyclic, or a polycyclic fused system. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The cycloalkyl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. For example, such cycloalkyl groups may be optionally substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl or di(C₁-C₆)alkylamino(C₁-C₆)alkyl.

By “aryl” is meant an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-, di-, or trisubstituted. Preferred aryl groups of the present invention are phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinyl or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. The aryl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. For example, such aryl groups may be optionally substituted with, for example, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl, mono (C₁-C₆)alkylamino (C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl, —COOH, —C(═O)O(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)N(mono- or di-C₁-C₆ alkyl), —S(C₁-C₆ alkyl), —SO₂(C₁-C₆ alkyl), —O—C(═O) (C₁-C₆ alkyl), —NH—C(═O)—(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)-C(═O)—(C₁-C₆ alkyl), —NH—SO₂—(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)-SO₂—(C₁-C₆ alkyl), —NH—C(═O)NH₂, —NH—C(═O)N(mono- or di-C₁-C₆ alkyl), —NH(C₁-C₆ alkyl)-C(═O)—NH₂ or —NH(C₁-C₆ alkyl)-C(═O)—N-(mono- or di-C₁-C₆ alkyl).

By “heteroaryl” is meant one or more aromatic ring systems of 5-, 6-, or 7-membered rings which includes fused ring systems of 9-11 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur. Preferred heteroaryl groups of the present invention include pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide. The heteroaryl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. For example, such heteroaryl groups may be optionally substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino, di(C₁-C₆) alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆) alkyl, mono (C₁-C₆) alkylamino (C₁-C₆) alkyl or di(C₁-C₆) alkylamino (C₁-C₆) alkyl, —COOH, —C(═O)O(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)N(mono- or di-C₁-C₆ alkyl), —S(C₁-C₆ alkyl), —SO₂(C₁-C₆ alkyl), —O—C(═O) (C₁-C₆ alkyl), —NH—C(═O)—(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)-C(═O)—(C₁-C₆ alkyl), —NH—SO₂—(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)-SO₂—(C₁-C₆ alkyl), —NH—C(═O)NH₂, —NH—C(═O)N(mono- or di-C₁-C₆ alkyl), —NH(C₁-C₆ alkyl)-C(═O)—NH₂ or —NH(C₁-C₆ alkyl)-C(═O)—N-(mono- or di-C₁-C₆ alkyl).

By “heterocycle”, “heterocycloalkyl” or “heterocyclyl” is meant one or more carbocyclic ring systems of 3-, 4-, 5-, 6-, or 7-membered rings which includes fused ring systems of 9-11 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur. Preferred heterocycles of the present invention include morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, azepanyl, diazepanyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide and homothiomorpholinyl S-oxide. The heterocycle groups herein maybe unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. For example, such heterocycle groups may be optionally substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino (C₁-C₆) alkyl, mono (C₁-C₆) alkylamino (C₁-C₆) alkyl, di(C₁-C₆) alkylamino (C₁-C₆) alkyl or ═O.

All patents and publications referred to herein are hereby incorporated by reference for all purposes.

Structures were named using Name Pro IUPAC Naming Software, version 5.09, available from Advanced Chemical Development, Inc., 90 Adelaide Street West, Toronto, Ontario, M5H 3V9, Canada.

The present invention may be better understood with reference to the following examples. These examples are intended to be representative of specific embodiments of the invention, and are not intended as limiting the scope of the invention.

CHEMISTRY EXAMPLES

The following detailed examples describe how to prepare the various compounds and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.

Preparation 1 tert-Butyl (1S)-3-bromo-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate (III)

N-methyl-morpholine (5.83 Ml, 53 mmole, 1.05 eq.) is added to (2S)-2-[(tert-butoxycarbonyl) amino]-3-(3,5-difluorophenyl) propanoic acid (II, 15 g, 50 mmole) in THF (100 mL) and the reaction is cooled to −78°. Isobutyl chloroformate (6.87 mL, 53 mmole, 1.05 eq.) is added rapidly. The cold bath is then removed and the mixture stirred for 1 hr. The reaction was monitored by TLC to insure completion of the reaction and the mixture is then filtered and washed with dry THF (50 ml) and kept cold in the filtered flask at −20°.

In a ice-salt bath is placed a 500 ml graduate cylinder containing ether (200 mL) and aqueous potassium hydroxide (40%, 60 ml). 1-methyl-3-nitro-1-nitrosoguanidine (5.6 g, 106 mmole, 2.1 eq.) is added slowly with stirring and temperature kept below zero degree. The mixture turned yellow and the bubbling lasted for 10 minutes. The stirring is stopped and without mixing the layers, the top diazomethane ethereal layer is transferred with non-ground tip pipette into the stirred mixed anhydride mixture at −20°. The reaction is monitored by TLC (ethyl acetate/hexane, 50/50; R_(f)=0.69). After 1 hour nitrogen is then bubbled into the mixture. The solvent is removed under reduced pressure (with heat) and the mixture is partitioned between ether and water. The phases are separated, the organic phase is washed with bicarbonate, saline, dried over anhydrous sodium sulfate, filtered, and solvent removed under reduced pressure (with heat). The residue is dissolved in ether (100 mL) and hydrobromous acid (48%, 15 mL, 135 mmole, 2.7 eq,) is added at −20°, the cold bath is removed and the mixture is stirred for another half hour. The reaction is monitored by TLC (ethyl acetate/hexane, 50/50; R_(f)=0.88). The mixture is partitioned between ether and water, washed with bicarbonate, saline, dried over anhydrous sodium sulfate, filtered, and the solvent removed. The residue is recrystallized from ethanol to give the title compound, TLC (ethyl acetate/hexane, 50/50) R_(f)=0.88; MS (MH⁺)=379.3

Preparation 2 tert-Butyl (1S, 2S)-3-bromo-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate (IV)

Sodium borohydride (1.32 g, 34.9 mmole, 1.1 eq.) is added to tert-Butyl (1S)-3-bromo-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate (III, PREPARATION 1, 12 g, 31.75 mmole) dissolved in absolute alcohol (500 mL) −78°. The reaction mixture is stirred for 30 minutes and monitored by TLC (ethyl acetate/hexane, 20/80; R_(f)=0.2). The mixture is quenched with water (10 mL) and the solvent removed under reduced pressure with heat (not exceeding 30°) to dryness. The solid is partitioned between dichloromethane and water, washed with saline, dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to give the title compound, TLC (ethyl acetate/hexane, 20/80) R_(f)=0.2; MS (MH⁺)=381.2

Preparation 3 tert-Butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V)

tert-Butyl (1S, 2S)-3-bromo-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate (IV, PREPARATION 2) is dissolved in absolute alcohol (150 mL) and ethyl acetate (100 mL) and potassium hydroxide (2.3 g, 34.9 mmole, 1.1 eq.) in ethyl alcohol (85%, 5 mL) is added at −20°. The cold bath is then removed and the mixture stirred for 30 minutes. The reaction is monitored by TLC (ethyl acetate/hexane, 20/80). When the reaction is complete, it is diluted with dichloromethane and extracted, washed with water, saline, dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The crude material is purified by flash chromatography on silica gel to give the title compound, TLC (ethyl acetate/hexane, 20/80) R_(f)=0.3; MS (MH⁺)=300.4.

Preparation 4: tert-Butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-(triflurormethyl)benzyl)amino]-propylcarbamate

tert-Butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (PREPARATION 3, 8.5 g, 28.4 mmole) is mixed with isopropanol (145 ml). The reaction flask is charged with 3-(trifluoromethyl) benzylamine. The reaction mixture is heated to reflux for 3 hours, HPLC analysis indicates complete disappearance of the epoxide. The reaction mixture is concentrated under reduced pressure and the residue is partitioned between ethyl acetate and aqueous hydrochloric acid. The organic phase is separated and washed with aqueous hydrochloric acid, bicarbonate, and saline then dried over sodium sulfate. Concentration under reduced pressure and recrystallization from hot hexane gives the title compound, MS (MH⁺) 475.

Preparation 5: tert-Butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{(tert-butyloxy)carbonyl-3-{(trifluoromethyl)benzyl}amino}propylcarbamate

To a solution of tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-(triflurormethyl)benzyl)-amino]propylcarbamate (PREPARATION 4, 6.2 g, 13.1 mmole) in THF (70 ml) at 0° is added di-tert-butyl pyrocarbonate (6.3 g, 28.9 mmole). The reaction mixture is stirred at 20-25° for 18 hours. The reaction mixture is diluted with diethyl ether and washed with bicarbonate, 0.5 M citric acid, and saline then dried over sodium sulfate and concentrated to give the title compound, MS (MNa⁺) 597.

Preparation 6: 3-iodo-5-(methoxycarbonyl)benzoic acid

To an ice-cold, stirred solution of commercially available 3-amino-5-(methoxycarbonyl)benzoic acid (5.19 g, 26.59 mmol) in 2 N hydrochloric acid (156 mL) was added a solution of sodium nitrite (1.84 g, 26.67 mmol) in water (10.8 mL). This mixture was then added dropwise to an ice-cold, stirred solution of potassium iodide (8.84 g, 53.25 mmol) in water (26.2 mL). After stirring for 35 min, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium thiosulfate, and saturated sodium chloride, dried (sodium sulfate), and concentrated under reduced pressure. Purification by flash column chromatography (silica, 50:50:2 hexanes/ethyl acetate/acetic acid) afforded the title compound (4.48 g, 55% yield) as an off-white solid. ESI-MS (m/z): 305 [M+H]⁺.

Preparation 7: 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoic acid

To a −70° C. solution of oxazole (4.0 g, 58 mmol) in tetrahydrofuran (100 mL) was added n-butyllithium (1.6 M in hexanes, 40 mL, 64 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 166 mL, 166 mmol) was added and the reaction mixture was warmed to 0° C. for 1 h. To this mixture was added 3-iodo-5-(methoxycarbonyl)benzoic acid (PREPARATION 6, 21.4 g, 55 mmol) and palladium(0) tetrakis(triphenylphosphine) (2.7 g, 2.34 mmol). The reaction mixture was heated at reflux for 1 h. The reaction mixture was diluted with ethyl acetate (300 mL), washed with water, and saturated sodium chloride. The organic layer was dried (sodium sulfate) and concentrated under reduced pressure. Purification by silica gel plug (10-33% ethyl acetate/hexanes) provided an oxazole (17.7 g, 97%) as a light yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 8.73 (t, J=2 Hz, 1H), 8.24 (t, J=2 Hz, 1H), 8.11 (t, J=2 Hz, 1H), 7.77 (d, J=1 Hz, 1H), 7.28 (d, J=1 Hz, 1H), 3.97 (s, 3H), 3.49 (m, 2H), 3.19 (m, 2H), 1.71 (m, 2H), 1.57 (m, 2H), 1.01 (m, 3H), 0.76 (m, 3H).

To a stirred solution of the ester from step 1 (17.7 g, 53.6 mmol) in tetrahydrofuran (50 mL), methanol (25 mL), and water (25 mL) was added lithium hydroxide monohydrate (6.92 g, 165 mmol). The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. The residue was partitioned between water (100 mL) and diethyl ether (100 mL). The aqueous layer was acidified to pH 4-5 with hydrochloric acid and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with saturated sodium chloride, dried (sodium sulfate), and concentrated under reduced pressure to one-half its original volume. The resulting precipitate was collected by filtration and washed with hexanes to provide the title compound (15.5 g, 91%) as an off-white solid: mp 131-133° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.72 (s, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 8.06 (d, J=1 Hz, 1H), 7.36 (d, J=1 Hz, 1H), 3.52 (m, 2H), 3.25 (m, 2H), 1.76 (m, 2H), 1.62 (m, 2H), 1.02 (m, 3H), 0.76 (m, 3H); APCI MS m/z 317 [M+H]⁺.

Preparation 8: (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(trifluoromethyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate dihydrochloride

To a solution of tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{(tert-butyloxy)carbonyl-3-{(trifluoromethyl)benzyl}amino}propylcarbamate (PREPARATION 5, 594 mg, 1.0 mmole) in DMF (2 mL) is added 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoic acid (PREPARATION 7, 316 mg, 1.0 mmole), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (210 mg, 1.1 mmole), and 4-(dimethylamino)pyridine (146 mg, 1.2 mmole). After ˜36 hours, the reaction mixture is diluted with ethyl acetate and washed with bicarbonate (2×) and brine (4×) then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate is purified on silica gel by flash chromatography using a gradient solvent of ethyl acetate/hexane (20/80 to 50/50) to give (1R,2S)-2-[(tert-butoxycarbonyl)amino]-1-({(tert-butoxycarbonyl)[3-(trifluoromethyl)benzyl]amino}methyl)-3-(3,5-difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate, MS (MNa⁺) 895.

(1R,2S)-2-[(tert-butoxycarbonyl)amino]-1-({(tert-butoxycarbonyl)[3-(trifluoromethyl)benzyl]amino}methyl)-3-(3,5-difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate (482 mg, 0.55 mmole) is dissolved in hydrochloric acid/dioxane (4N, 3 ml) is stirred for 1 hour at 20-25°. The solvent is then removed under reduced pressure to give the title compound, MS (MH⁺) 673.

Preparation 9: N˜1˜-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-(1,3-oxazol-2-yl)-N˜3˜,N˜3˜-dipropyl-N˜1˜-[3-(trifluoromethyl)benzyl]-isophthalamide hydrochloride

To a solution of tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-(trifluorormethyl)benzyl)amino]propylcarbamate (PREPARATION 4, 393 mg, 0.83 mmole) in DMF (2 mL) is added 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoic acid (PREPARATION 7, 262 mg, 0.83 mmole), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (175 mg, 0.91 mmole), and 4-(dimethylamino)pyridine (122 mg, 1.0 mmole). After ˜18 hours, the reaction mixture is diluted with ethyl acetate and washed with bicarbonate (2×) and brine (4×) then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate is purified on silica gel by flash chromatography using a gradient solvent of ethyl acetate/hexane (50/50 to 70/30) to give tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoyl][3-(trifluoromethyl)benzyl]amino}-2-hydroxypropylcarbamate, MS (MH⁺) 773.

tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoyl][3-(trifluoromethyl)benzyl]amino}-2-hydroxypropylcarbamate (226 mg, 0.29 mmole) is dissolved in hydrochloric acid/dioxane (4N, 2 ml) is stirred for 20 minutes at 20-25°. The solvent is then removed under reduced pressure and the crude material purified by reverse phase HPLC using a gradient aolvent of acetonitrile/water with 0.5% trifluoroacetic acid. The trifluoroacetic acid salt obtained is converted to the hydrochloric salt by treatment with HCl in methanol (1.25 M, 5 mL). Concentration under reduced pressure gives the title compound, MS (MH⁺) 673.

The following compounds are prepared essentially according to the procedures described in the schemes, charts, examples and preparations set forth herein.

Comp [M + # Structure Compound Name(s) H]+ 9

N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(butylsulfonyl)-N¹-(3-ethylbenzyl)-D-alaninamidedihydrochloride 526 10

N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3-ethylbenzyl)-N²[(benzyloxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D-alaninamide trifluoroacetate 702 11

N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]-D-alaninamide hydrochloride 568 12

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-[(methylsulfonyl)amino]-1,3-thiazole-5-carboxamide 539 13

N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]-L-alaninamidebis(trifluoroacetate) 568 14

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(butylsulfonyl)-N-(3-ethylbenzyl)propanamidehydrochloride 511 15

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)propanoatedihydrochloride 511 16

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoatedihydrochloride 633 17

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-ethylphenyl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoatedihydrochloride 659 18

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(trifluoromethyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoatedihydrochloride 673 19

N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N\(u)1\(d)-(3-ethylbenzyl)-5-(1,3-oxazol-2-yl)-N³,N³-dipropylisophthalamidehydrochloride 633 20

N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-(1,3-oxazol-2-yl)-N³,N³-dipropyl-N¹-[3-(trifluoromethyl)benzyl]iso-phthalamide hydrochloride 673 21

N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-(1,3-oxazol-2-yl)-N³,N³-dipropyl-N¹-[3-(trifluoromethyl)benzyl]iso-phthalamide 673 22

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-ethynylphenyl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate 655 23

N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(butylsulfonyl)-N¹-(3-ethylbenzyl)-N²[(methoxy)carbonyl]-D-alaninamide dihydrochloride 584 24 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-{[(2- hydroxyethyl)amino]sulfonyl}benzoate 26 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(2-isobutyl-1,3-thiazol-5- yl)methyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-ethynylbenzoate 28 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- isopropylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- ethynylbenzoate 30 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- isopropylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-(1,3- oxazol-2-yl)benzoate 32 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-{[(2-hydroxy- 1,1-dimethylethyl)amino]sulfonyl}benzoate 34 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-(4-methyl-1,3- oxazol-2-yl)benzoate 36 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(2-isobutyl-1,3-thiazol-5- yl)methyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2- yl)benzoate 38 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-{[(3- hydroxypropyl)amino]sulfonyl}benzoate hydrochloride 40 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- propylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 42 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[butyl(methyl)amino]carbonyl}-5- methylbenzoate 44 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethynylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- ethynylbenzoate 46 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(3-isobutylisoxazol-5- yl)methyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-ethynylbenzoate 48

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(dimethyl-amino)sulfonyl]-5-[(dipropyl-amino)carbonyl]benzoate 50

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(dipropyl-amino)carbonyl]-5-(1,3-oxazol-2-yl)benzoatehydrochloride 52

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(5-formyl-2-thienyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 54

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-iodobenzyl)amino]methyl}propyl 3-bromo-5-[(dipropyl-amino)carbonyl]benzoate 56

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-({[(1R)-2-hydroxy-1-methylethyl]amino}sulfonyl)benzoate 58

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-isobutylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 60

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(trifluoromethyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-ethynylbenzoate 62 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[(2R)-2-(methoxymethyl)pyrrolidin-1- yl]carbonyl}-5-methylbenzoate hydrochloride 64 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-({[(1S)-2- hydroxy-1-methylethyl]amino}sulfonyl)benzoate 66 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[butyl(propyl)amino]carbonyl}-5- methylbenzoate 68 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(dibutylamino)carbonyl]-5-methylbenzoate 70 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(3-hydroxyprop-1-yn-1- yl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 72 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-{[(2S)-2- (hydroxymethyl)pyrrolidin-1-yl]sulfonyl}benzoate 74 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[butyl(ethyl)amino]carbonyl}-5- methylbenzoate 76 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethynylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-(1,3- oxazol-2-yl)benzoate 78 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[cyclohexyl(methyl)amino]carbonyl}-5- methylbenzoate 80 (1R,2S)-2-amino-1-({[3-(cyclopropylamino)benzyl]amino}methyl)-3-(3,5- difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-ethynylbenzoate 82 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(3- thienyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 84 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3- (trifluoromethyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- (1,3-oxazol-2-yl)benzoate 86 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-(piperazin-1- ylsulfonyl)benzoate dihydrochloride 88 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- iodophenyl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 90 (1R,2S)-2-amino-1-{[(3-sec-butylbenzyl)amino]methyl}-3-(3,5- difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 92 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-(3- methylisoxazol-4-yl)benzoate hydrochloride 94 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-isobutylisoxazol-5- yl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3- oxazol-2-yl)benzoate 96 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethylphenyl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- (1,3-oxazol-2-yl)benzoate 98 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-[(dipropylamino)carbonyl]-6- methylisonicotinate 100 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3- {[(cyclopropylmethyl)(propyl)amino]carbonyl}-5-methylbenzoate 102 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-(1,3- oxazol-2-yl)benzoate 104 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethynylphenyl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]- 5-(1,3-oxazol-2-yl)benzoate 106 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(aminosulfonyl)-5- [(dipropylamino)carbonyl]benzoate 108 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-[({3-[(1Z)-prop-1-en-1- yl]benzyl}amino)methyl]propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 110 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-(1H-pyrazol- 4-yl)benzoate hydrochloride 112 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-ethylphenyl)-1- methylethyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- ethynylbenzoate 114 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3- (trifluoromethyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 116 (1R,2S)-1-{[(3-allylbenzyl)amino]methyl}-2-amino-3-(3,5- difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 118 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethylphenyl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 120 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-ethylphenyl)-1- methylethyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2- yl)benzoate 122 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[ethyl(propyl)amino]carbonyl}-5- methylbenzoate 124 (1R,2S)-2-amino-1-({[3-(cyclopropylamino)benzyl]amino}methyl)-3-(3,5- difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 126 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethynylphenyl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]- 5-ethynylbenzoate 128 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-isobutylisoxazol-5- yl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 130 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(5-formyl-4-methyl-2- thienyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 132 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- isopropylbenzyl)amino]methyl}propyl 5-[(dipropylamino)carbonyl]nicotinate 134 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-[({3- [(methylsulfonyl)amino]benzyl}amino)methyl]propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 136 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(butylamino)carbonyl]-5-methylbenzoate 138 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(3- methylbutyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 140 (1R,2S)-2-amino-1-{[(biphenyl-3-ylmethyl)amino]methyl}-3-(3,5- difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 142 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethynylphenyl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]- 5-methylbenzoate 144 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-({[2- (methylamino)ethyl]amino}sulfonyl)benzoate hydrochloride 146 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-isobutylisoxazol-5- yl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- ethynylbenzoate 148

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(diallylamino)carbonyl]-5-methylbenzoate 150

(1R,2R)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(2-isobutyl-1,3-thiazol-5-yl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 152

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-ethylphenyl)-1-methyl-ethyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 154

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-{[(2-hydroxyethyl)amino]sulfonyl}-5-[(propylamino)carbonyl]benzoate 156

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-methyl-5-{[methyl(propyl)amino]carbonyl}benzoate 158

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-(phenylsulfonyl)-3-[(1-propylbutyl)sulfonyl]alaninate hydrochloride 160

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(diethylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate 162

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-[(benzylamino)carbonyl]-3-[(1-propylbutyl)sulfonyl]alaninatetrifluoroacetate 164

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-pyridin-3-ylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 166 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-[(dipropylamino)carbonyl]nicotinate 1- oxide 168 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(3-forrnyl-2- furyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 170 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-(1-methyl-1H- imidazol-2-yl)benzoate 172 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(diethylamino)carbonyl]-5-methylbenzoate 174 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3- (ethylsulfinyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 176 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[butyl(ethyl)amino]sulfonyl}propanoate 178 (1R,2S)-2-amino-1-{[(3-cyanobenzyl)amino]methyl}-3-(3,5- difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 180 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]propanoate hydrochloride 182 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[isobutyl(methyl)amino]carbonyl}-5- methylbenzoate 184

186

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-pyridin-2-ylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 188

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-iodobenzyl)amino]methyl}propyl 2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxylate 190

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-[({3-[methyl(methylsulfonyl)amino]benzyl}amino)methyl]propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 192

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-(3-phenylpro-panoyl)-3-[(1-propylbutyl)sulfonyl]alaninatetrifluoroacetate 194 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3- (ethylsulfonyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 196 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(5-chloro-2-thienyl)sulfonyl]-3-[(1- propylbutyl)sulfonyl]alaninate hydrochloride 198 (1R,2S)-1-({[3-(5-acetyl-2-thienyl)benzyl]amino}methyl)-2-amino-3-(3,5- difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 200 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(sec-butylamino)carbonyl]-5- methylbenzoate 202 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(1,3-oxazol-2-yl)benzoate hydrochloride 204 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-methyl-5-{[methyl(2- phenylethyl)amino]carbonyl}benzoate 206 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(3,5-dimethylisoxazol-4- yl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 208 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-methyl-5-{[methyl(prop-2-yn-1- yl)amino]carbonyl}benzoate 210 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[ethyl(methyl)amino]carbonyl}-5- methylbenzoate 212 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- {[(dimethylamino)carbonyl]oxy}benzyl)amino]methyl}propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 214 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[benzyl(methyl)amino]carbonyl}-5- methylbenzoate 216 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[sec-butyl(propyl)amino]carbonyl}-5- methylbenzoate 218 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(4-methyl-2- thienyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 220 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-[({3- [(methoxycarbonyl)(methyl)amino]benzyl}amino)methyl]propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 222 (1R,2S)-2-amino-1-({[3-(trifluoromethyl)benzyl]amino}methyl)-3-(2,3,5- trifluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 224 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(diisobutylamino)carbonyl]-5- methylbenzoate 226 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-methyl-5-{[methyl(2-pyridin-2- ylethyl)amino]carbonyl}benzoate 228 (1R,2S)-2-amino-3-(3-fluoro-5-hydroxyphenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate hydrochloride 230 (1R,2S)-2-amino-3-(3-chloro-5-fluorophenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 232 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- iodobenzyl)amino]methyl}propyl 4-hydroxy-3-(pyrrolidin-1- ylcarbonyl)benzoate 234 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-oxo-D-prolyl-3-[(1- propylbutyl)sulfonyl]alaninate hydrochloride 236

238

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-pyridin-4-ylbenzyl)amino]methyl}propyl 3-[(dipropyl-amino)carbonyl]-5-methylbenzoate 240

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-[({3-[(dimethylamino)sulfonyl]benzyl}amino)methyl]propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 242 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(6-methoxy-1,2,3,4- tetrahydronaphthalen-1-yl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 244 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(phenylacetyl)-3-[(1- propylbutyl)sulfonyl]alaninate 246 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(azepan-1-ylcarbonyl)-5-methylbenzoate 248 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-[({3- [(methoxycarbonyl)amino]benzyl}amino)methyl]propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 250 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-oxo-L-prolyl-3-[(1- propylbutyl)sulfonyl]alaninate hydrochloride 252 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(isobutylamino)carbonyl]-5- methylbenzoate 254 4-[((1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl)oxy]-4-oxo-3-{[(1- propylbutyl)sulfonyl]methyl}butanoic acid trifluoroacetate 256 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[methyl(methylsulfonyl)amino]benzoate 25 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl-N-(3-ethylbenzyl)- 5-{[(2-hydroxyethyl)amino]sulfonyl}-N′,N′-dipropylisophthalamide 27 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-ethynyl-N-[(2- isobutyl-1,3-thiazol-5-yl)methyl]-N′,N′-dipropylisophthalamide 29 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-ethynyl-N-(3- isopropylbenzyl)-N′,N′-dipropylisophthalamide 31 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- isopropylbenzyl)-5-(1,3-oxazol-2-yl)-N′,N′-dipropylisophthalamide 33 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 5-{[(2-hydroxy-1,1-dimethylethyl)amino]sulfony}-N′,N′- dipropylisophthalamide 35 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 5-(4-methyl-1,3-oxazol-2-yl)-N′,N′-dipropylisophthalamide 37 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[(2-isobutyl-1,3- thiazol-5-yl)methyl]-5-(1,3-oxazol-2-yl)-N′,N′-dipropylisophthalamide 39 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl) 5-{[(3-hydroxypropyl)amino]sulfonyl}-N′,N′-dipropylisophthalamide hydrochloride 41 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N′,N′- dipropyl-N-(3-propylbenzyl)isophthalamide 43 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-butyl-N-(3- ethylbenzyl)-N′,5-dimethylisophthalamide 45 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-ethynyl-N-(3- ethynylbenzyl)-N′,N′-dipropylisophthalamide 47 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-ethynyl-N-[(3- isobutylisoxazol-5-yl)methyl]-N′,N′-dipropylisophthalamide 49 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5- [(dimethylamino)sulfonyl]-N-(3-ethylbenzyl)-N′,N′-dipropylisophthalamide 51 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 5-(1,3-oxazol-2-yl)-N′,N′-dipropylisophthalamide hydrochloride 53 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[3-(5-formyl-2- thienyl)benzyl]-5-methyl-N′,N′-dipropylisophthalamide 55 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-bromo-N-(3- iodobenzyl)-N′,N′-dipropylisophthalamide 57 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 5-({[(1R)-2-hydroxy-1-methylethyl]amino}sulfonyl)-N′,N′- dipropylisophthalamide 59 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- isobutylbenzyl)-5-methyl-N′,N′-dipropylisophthalamide 61 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-ethynyl-N′,N′- dipropyl-N-[3-(trifluoromethyl)benzyl]isophthalamide 63 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-{[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}-5-methylbenzamide hydrochloride 65 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 5-({[(1S)-2-hydroxy-1-methylethyl]amino}sulfonyl)-N′,N′- dipropylisophthalamide 67 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-butyl-N-(3- ethylbenzyl)-5-methyl-N′-propylisophthalamide 69 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′,N′-dibutyl-N-(3- ethylbenzyl)-5-methylisophthalamide 71 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[3-(3- hydroxyprop-1-yn-1-yl)benzyl]-5-methyl-N′,N′-dipropylisophthalamide 73 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl) 5-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl}-N′,N′- diproplisophthalamide 75 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-butyl-N′-ethyl- N-(3-ethylbenzyl)-5-methylisophthalamide 77 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3 - ethynylbenzyl)-5-(1,3-oxazol-2-yl)-N′,N′-dipropylisophthalamide 79 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-cyclohexyl-N- (3-ethylbenzyl)-N′,5-dimethylisophthalamide 81 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[3- (cyclopropylamino)benzyl]-5-ethynyl-N′,N′-dipropylisophthalamide 83 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N′,N′- dipropyl-N-[3-(3-thienyl)benzyl]isophthalamide 85 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-(1,3-oxazol-2- yl)-N′,N′-dipropyl-N-[3-trifluoromethyl)benzyl]isophthalamide 87 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 5-(piperazin-1-ylsulfonyl)-N′,N′-dipropylisophthalamide dihydrochloride 89 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[1-(3- iodophenyl)cyclopropyl]-5-methyl-N′,N′-dipropylisophthalamide 91 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3 -sec- butylbenzyl)-5-methyl-N′,N′-dipropylisophthalamide 93 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 5-(3-methylisoxazol-4-yl)-N′,N′-dipropylisophthalamide hydrochloride 95 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[1-(3- isobutylisoxazol-5-yl)cyclopropyl]-5-(1,3-oxazol-2-yl)-N′,N′- dipropylisophthalamide 97 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[1-(3- ethylphenyl)cyclopropyl]-5-(1,3-oxazol-2-yl)-N′,N′-dipropylisophthalamide 99 N⁴-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N⁴-(3- ethylbenzyl)-6-methyl-N²,N²-dipropylpyridine-2,4-dicarboxamide 101 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′- (cyclopropylmethyl)-N-(3-ethylbenzyl)-5-methyl-N′-propylisophthalamide 103 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- methoxybenzyl)-5-(1,3-oxazol-2-yl)-N′,N′-dipropylisophthalamide 105

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[1-(3-ethynylphenyl)cyclopropyl]-5-(1,3-oxazol-2-yl)-N′,N′-dipropylisophthalamide 107

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-(amino-sulfonyl)-N-(3-ethylbenzyl)-N′,N′-dipropylisophthalamide 109

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-{3-[(1Z)-prop-1-en-1-yl]benzyl}-N′,N′-dipropylisophthalamide 111

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-N′,N′-dipropyl-5-(1H-pyrazol-4-yl)isophthalamidedihydrochloride 113

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[1-(3-ethylphenyl)-1-methylethyl]-5-ethynyl-N′,N′-dipropylisophthalamide 115

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N′,N′-dipropyl-N-[3-(trifluoromethyl)benzyl]isophthalamide 117

N-(3-allylbenzyl)-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxy-butyl]-5-methyl-N′,N′--dipropylisophthalamide 119

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[1-(3-ethylphenyl)cyclopropyl]-5-methyl-N′,N′-dipropylisophthalamide 121 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[1-(3- ethylphenyl)-1-methylethyl]-5-(1,3-oxazol-2-yl)-N′,N′-dipropylisophthalamide 123 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-ethyl-N-(3- ethylbenzyl)-5-methyl-N′-propylisophthalamide 125 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[3- (cyclopropylamino)benzyl]-5-methyl-N′,N′-dipropylisophthalamide 127 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-ethynyl-N-[1-(3- ethynylphenyl)cyclopropyl]-N′,N′-dipropylisophthalamide 129 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[1-(3- isobutylisoxazol-5-yl)cyclopropyl]-5-methyl-N′,N′-dipropylisophthalamide 131 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[3-(5-formyl-4- methyl-2-thienyl)benzyl]-5-methyl-N′,N′-dipropylisophthalamide 133 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- isopropylbenzyl)-N′,N′-dipropylpyridine-3,5-dicarboxamide 135 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-{3- [(methylsulfonyl)amino]benzyl}-N′,N′-dipropylisophthalamide 137 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-butyl-N-(3- ethylbenzyl)-5-methylisophthalamide 139 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-[3-(3- methylbutyl)benzyl]-N′,N′-dipropylisophthalamide 141 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(biphenyl-3- ylmethyl)-5-methyl-N′,N′-dipropylisophthalamide 143 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[1-(3- ethynylphenyl)cyclopropyl]-5-methyl-N′,N′-dipropylisophthalamide 145 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 5-({[2-(methylamino)ethyl]amino}sulfonyl)-N′,N′-dipropylisophthalamide hydrochloride 147 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-ethynyl-N-[1-(3- isobutylisoxazol-5-yl)cyclopropyl]-N′,N′-dipropylisophthalamide 149 N,N-diallyl-N′-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-(3- ethylbenzyl)-5-methylisophthalamide 151 N-[(2R,3R)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[1-(2-isobutyl- 1,3-thiazol-5-yI)cyclopropyl]-5-methyl-N′,N′-dipropylisophthalamide 153 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[1-(3- ethylphenyl)-1-methylethyl]-5-methyl-N′,N′-dipropylisophthalamide 155 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 5-{[(2-hydroxyethyl)amino]sulfonyl}-N′-propylisophthalamide 157 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- N′,5-dimethyl-N′-propylisophthalamide 159 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3- ethylbenzyl)-N²-(phenylsulfonyl)-3-[(1-propylbutyl)sulfonyl]alaninamide hydrochloride 161 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′,N′-diethyl-N-(3- ethylbenzyl)-5-(1,3-oxazol-2-yl)isophthalamide 163 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N²- [(benzylamino)carbonyl]-N¹-(3-ethylbenzyl)-3-[(1- propylbutyl)sulfonyl]alaninamide trifluoroacetate (salt) 165 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N′,N′- dipropyl-N-(3-pyridin-3-ylbenzyl)isophthalamide 167 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- N′,N′-dipropylpyridine-3,5-dicarboxamide 1-oxide 169 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-ethyl-N-[3-(3- formyl-2-furyl)benzyl]-5-methyl-N′-propylisophthalamide 171 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 5-(1-methyl-1H-imidazol-2-yl)-N′,N′-dipropylisophthalamide 173 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′,N′-diethyl-N-(3- ethylbenzyl)-5-methylisophthalamide 175 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[3- (ethylsulfinyl)benzyl]-5-methyl-N′,N′-dipropylisophthalamide 177 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3- {[butyl(ethyl)amino]sulfonyl}-N-(3-ethylbenzyl)propanamide 179 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-cyanobenzyl)- 5-methyl-N′,N′-dipropylisophthalamide 181 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-[(1-propylbutyl)sulfonyl]propanamide hydrochloride 183 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- N′-isobutyl-N′,5-dimethylisophthalamide 185

187

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N′,N′-dipropyl-N-(3-pyridin-2-ylbenzyl)isophthalamide 189

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-iodobenzyl)-2-[(methyl-sulfonyl)amino]-1,3-oxazole-4-carboxamide 191

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-{3-[methyl(methyl-sulfonyl)amino]benzyl}-N′,N′-dipropylisophthalamide 193

N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3-ethylbenzyl)-N²-(3-phenylpropanoyl)-3-[(1-propylbutyl)sulfonyl]alaninamide trifluoroacetate(salt) 195

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[3-(ethyl-sulfonyl)benzyl]-5-methyl-N′,N′-dipropylisophthalamide 197

N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N²-[(5-chloro-2-thienyl)sulfonyl]-N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]alaninamidehydrochloride 199 N-[3-(5-acetyl-2-thienyl)benzyl]-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2- hydroxybutyl]-5-methyl-N′,N′-dipropylisophthalamide 201 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-(sec-butyl)-N- (3-ethylbenzyl)-5-methylisophthalamide 203 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-(1,3-oxazol-2-yl)benzamide hydrochloride 205 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- N′,5-dimethyl-N′-(2-phenylethyl)isophthalamide 207 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[3-(3,5- dimethylisoxazol-4-yl)benzyl]-5-methyl-N′,N′-dipropylisophthalamide 209 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- N′,5-dimethyl-N′-prop-2-yn-1-ylisophthalamide 211 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-ethyl-N-(3- ethylbenzyl)-N′,5-dimethylisophthalamide 213 3-[([(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]{3- [(dipropylamino)carbonyl]-5-methylbenzoyl}amino)methyl]phenyl dimethylcarbamate 215 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-benzyl-N-(3- ethylbenzyl)-N′,5-dimethylisophthalamide 217 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-(sec-butyl)-N- (3-ethylbenzyl)-5-methyl-N′-propylisophthalamide 219 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-[3-(4- methyl-2-thienyl)benzyl]-N′,N′-dipropylisophthalamide 221 methyl {3-[([(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]{3- [(dipropylamino)carbonyl]-5- methylbenzoyl}amino)methyl]phenyl}methylcarbamate 223 N-[(2R,3S)-3-amino-2-hydroxy-4-(2,3,5-trifluorophenyl)butyl]-5-methyl-N′,N′- dipropyl-N-[3-(trifluoromethyl)benzyl]isophthalamide 225 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- N′,N′-diisobutyl-5-methylisophthalamide 227 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- N′,5-dimethyl-N′-(2-pyridin-2-ylethyl)isophthalamide 229 N-[(2R,3S)-3-amino-4-(3-fluoro-5-hydroxyphenyl)-2-hydroxybutyl]-N-(3- methoxybenzyl)-5-methyl-N′,N′-dipropylisophthalamide hydrochloride 231 N¹-[(2R,3S)-3-amino-4-(3-chloro-5-fluorophenyl)-2-hydroxybutyl]-N¹-(3- methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 233 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-hydroxy-N-(3- iodobenzyl)-3-(pyrrolidin-1-ylcarbonyl)benzamide 235 5-oxo-D-prolyl-N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]- N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]alaninamide hydrochloride 237

239

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxy-butyl]-5-methyl-N′,N′-dipropyl-N-(3-pyridin-4-ylbenzyl)isophthalamide 241

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxy-butyl]-N-{3-[(dimethyl-amino)sulfonyl]benzyl}-5-methyl-N′,N′-dipropylisophthalamide 243

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxy-butyl]-N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-5-methyl-N′,N′-dipropylisophthalamide 245 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3- ethylbenzyl)-N²-(phenylacetyl)-3-[(1-propylbutyl)sulfonyl]alaninamide 247 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(azepan-1- ylcarbonyl)-N-(3-ethylbenzyl)-5-methylbenzamide 249 methyl {3-[([(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]{3- [(dipropylamino)carbonyl]-5-methylbenzoyl}amino)methyl]phenyl}carbamate 251 5-oxo-L-prolyl-N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]- N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]alaninamide hydrochloride 253 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- N¹-isobutyl-5-methylisophthalamide 255 4-[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]-4-oxo-3-{[(1-propylbutyl)sulfonyl]methyl}butanoic acid trifluoroacetate (salt) 257 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-[methyl(methylsulfonyl)amino]benzamide 258 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[ethyl(isopropyl)amino]carbonyl}-5- methylbenzoate 260 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-(2-thienyl)propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 262 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[(2- hydroxyethyl)(propyl)amino]sulfonyl}propanoate 264 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[isopropyl(methyl)amino]carbonyl}-5- methylbenzoate 266 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-[(methylsulfonyl)amino]-1,3-thiazole-4- carboxylate 268 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[allyl(cyclopentyl)amino]carbonyl}-5- methylbenzoate 270

272

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(3-methylbutyl)sulfonyl]propanoate 274

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(5-methyl-2-thienyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 276

(1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-(3-methoxyphenyl)propyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 278 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(1- methylhexyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 280 (1R,2S)-2-amino-1-({[1-(aminocarbonyl)cyclohexyl]amino}methyl)-3-(3,5- difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 282 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(2E)-hex-2-en-1- ylamino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 284 (1R,2S)-2-amino-3-(4-fluorophenyl)-1-{[(3- methoxybenzyl)amino]methy}propyl 3-[(dipropylamino)carbonyl]-5- methylbenozate 286 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-hydroxyisoxazole-5-carboxylate 288 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-[({3-[(1E)-hex-1-en-1- yl]benzyl}amino)methyl]propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 290 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(isopropylamino)carbonyl]-5- methylbenzoate 292 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-(2-thienyl)propyl 3- (aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 294 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- iodobenzyl)amino]methyl}propyl [3-(2-amino-2-oxoethoxy)phenyl]acetate 296 (1R,2S)-2-amino-3-(3-bromophenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 298 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(2-ethylhexyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 300 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(6-methoxypyridin-3- yl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 302 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(2,4-dimethoxypyrimidin-5- yl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 304 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(2-ethylbutanoyl)benzoate 306 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(4-hydroxypiperidin-1-yl)carbonyl]-5- methylbenzoate 308 (1R,2S)-2-amino-3-(3-bromophenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 310 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- iodobenzyl)amino]methyl}propyl 4-[2′-(aminocarbonyl)biphenyl-4-yl]-4- oxobutanoate 312

314

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(3-hydroxypiperidin-1-yl)carbonyl]-5-methylbenzoate 316

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-hydroxy-1-phenylpropyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 318

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-{[[2-(dimethyl-amino)ethyl](ethyl)amino]carbonyl}-5-methylbenzoate 320 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-methyl-4H,6H-pyrrolo[1,2- a][4,1]benzoxazepine-4-carboxylate 322 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (5-acetyl-2-thienyl)acetate 324 (1R,2S)-2-amino-3-(3,5-dichlorophenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 326 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(diisopropylamino)carbonyl]-5- methylbenzoate 328 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(methylsulfonyl)amino]benzoate 330 (1R,2S)-2-amino-3-(4-chlorophenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 332 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- iodobenzyl)amino]methyl}propyl [4-(2-oxopyrrolidin-1-yl)phenyl]acetate 334 (1R,2S)-2-amino-3-(3-chloro-5-fluorophenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)sulfonyl]propanoate 336 (1R,2S)-2-amino-3-(3-chloro-5-fluorophenyl)-1-{[(3- methylbutyl)amino]methyl}propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 338

340 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[(1-methyl-1H-imidazol-4- yl)sulfonyl]amino}benzoate trihydrochloride 342 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-[(pentylamino)methyl]propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 344 (1R,2S)-2-amino-3-(4-fluorophenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 346 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(3-chloro-5-fluorophenyl)propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 348 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[cyclohexyl(ethyl)amino]carbonyl}-5- methylbenzoate 350 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[2-({[(2,4- difluorophenyl)amino]carbonyl}oxy)ethyl]amino}methyl)propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 352 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[(2S)-2-(methoxymethyl)pyrrolidin-1- yl]carbonyl}-5-methylbenzoate hydrochloride 354 (1R,2S)-2-amino-3-(3-fluoro-4-methylphenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 356 (1R,2S)-2-amino-3-(3-bromophenyl)-1-{[(3-methylbutyl)amino]methyl}propyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 358 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2,8-dimethylquinoline-3-carboxylate 360 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(6- hydroxyhexyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 362 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(2R)-2- hydroxypropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 364 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 3-[(1- propylbutyl)sulfonyl]propanoate 366 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[(2-hydroxy-1,1- dimethylethyl)amino]sulfonyl}benzoate 368 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(4- phenylbutyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 370 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- iodobenzyl)amino]methyl}propyl 7-(1H-imidazol-1-yl)-5,6-dihydronaphthalene- 2-carboxylate 372 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(acetylamino)-4-methylbenzoate 374 (1R,2S)-2-amino-1-({[2-(aminosulfonyl)ethyl]amino}methyl)-3-(3,5- difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 376 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[2- (ethylthio)ethyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 378 (1R,2S)-2-amino-3-cyclohexyl-1-{[(3-methoxybenzyl)amino]methyl}propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 380 (1R,2S)-2-amino-1-{[benzyl(cyanomethyl)amino]methyl}-3-(3,5- difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 382 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(2- hydroxypropyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 384 (1R,2S)-2-amino-1-{[(3-butoxypropyl)amino]methyl}-3-(3,5- difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 386 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[2-(2-hydroxyethyl)piperidin-1- yl]carbonyl}-5-methylbenzoate 388

390

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(1-hydroxy-2-propylpentyl)benzoate 392

(1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(3-chloro-5-fluorophenyl)propyl3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 394 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-[(methylsulfonyl)amino]butanoate trifluoroacetate 396 (1R,2S)-2-amino-1-({[3-(1-benzothien-2-yl)benzyl]amino}methyl)-3-(3,5- difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 398 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(benzyloxy)isoxazole-5-carboxylate 400 (1R,2S)-2-amino-1-{[(cyclopropylmethyl)amino]methyl}-3-(3,5- difluorophenyl)propyl N-[(benzyloxy)carbonyl]-3-[(1- propylbutyl)sulfonyl]alaninate trifluoroacetate 402

404 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-(1H-pyrazol-1-yl)pentanoate 406 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 1-(2-furylmethyl)-5-oxopyrrolidine-3- carboxylate 408 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 2- ethylhexanoate hydrochloride 410 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(5- hydroxypentyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 412 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]piperidine-1- carboxylate 414 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-[(diethylamino)carbonyl]piperidine-1- carboxylate 416 (1R,2S)-2-amino-3-(pentafluorophenyl-1-({[3- (trifluoromethyl)benzyl]amino}methyl)propyl 3-bromo-5- [(dipropylamino)carbonyl]benzoate 418 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-[(methylsulfonyl)amino]benzoate 420

422 (1R,2S)-2-amino-3-(3-bromophenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)sulfonyl]propanoate 424 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-(2-thienyl)propyl 3- [(dipropylamino)sulfonyl]propanoate 426 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethoxypropyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 428 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(2-thienyl)propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 430

432 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-hydroxy-4-(phenylsulfonyl)butanoate hydrochloride 434 (1R,2S)-2-amino-3-(3,5-dichlorophenyl)-1-{[(3- methylbutyl)amino]methyl}propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 436 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-[3- (trifluoromethoxy)phenyl]propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 259 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-ethyl-N-(3- ethylbenzyl)-N′-isopropyl-5-methylisophthalamide 261 N-[(2R,3S)-3-amino-2-hydroxy-4-(2-thienyl)butyl]-N-(3-methoxybenzyl)-5- methyl-N′,N′-dipropylisophthalamide 263 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-{[(2-hydroxyethyl)(propyl)amino]sulfonyl}propanamide 265 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- N′-isopropyl-N′,5-dimethylisophthalamide 267 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide 269 N-allyl-N′-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N- cyclopentyl-N′-(3-ethylbenzyl)-5-methylisophthalamide 271

273 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-[(3-methylbutyl)sulfonyl]propanamide 275 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-[3-(5- methyl-2-thienyl)benzyl]-N′,N′-dipropylisophthalamide 277 N¹-[(2R,3S)-3-amino-2-hydroxy-4-(3-methoxyphenyl)butyl]-N¹-(3- methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 279 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-(1- methylhexyl)-N′,N′-dipropylisophthalamide 281 N-[1-(aminocarbonyl)cyclohexyl]-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2- hydroxybutyl]-5-methyl-N′,N′-dipropylisophthalamide 283 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[(2E)-hex-2-en- 1-yl]-5-methyl-N′,N′-dipropylisophthalamide 285 N-[(2R,3S)-3-amino-4-(4-fluorophenyl)-2-hydroxybutyl]-N-(3-methoxybenzyl)- 5-methyl-N′,N′-dipropylisophthalamide 287 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-hydroxyisoxazole-5-carboxamide 289 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-{3-[(1E)-hex-1- en-1-yl]benzyl}-5-methyl-N′,N′-dipropylisophthalamide 291 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- N′-isopropyl-5-methylisophthalamide 293 N¹-[(2R,3S)-3-amino-2-hydroxy-4-(2-thienyl)butyl]-N¹-(3-methoxybenzyl)- N³,N³-dipropylbenzene-1,3,5-tricarboxamide 295 2-(3-{2-[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- iodobenzyl)amino]-2-oxoethyl}phenoxy)acetamide 297 N-[(2R,3S)-3-amino-4-(3-bromophenyl)-2-hydroxybutyl]-N-(3-methoxybenzyl)- 5-methyl-N′,N′-dipropylisophthalamide 299 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(2-ethylhexyl)-5- methyl-N′,N′-dipropylisophthalamide 301 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[3-(6- methoxypyridin-3-yl)benzyl]-5-methyl-N′,N′-dipropylisophthalamide 303 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[3-(2,4- dimethoxypyrimidin-5-yl)benzyl]-5-methyl-N′,N′-dipropylisophtalamide 305 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-(2-ethylbutanoyl)benzamide 307 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-[(4-hydroxypiperidin-1-yl)carbonyl]-5-methylbenzamide 309 N¹- [(2R,3S)-3-amino-4-(3-bromophenyl)-2-hydroxybutyl]-N¹-(3- methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 311 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- iodobenzyl)amino]methyl}propyl 4-[2′-(aminocarbonyl)biphenyl-4-yl]-4- oxobutanoate 313 1-(3-{[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]carbonyl}-5-methylbenzoyl)-L-prolinamide 315 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-[(3-hydroxypiperidin-1-yl)carbonyl]-5-methylbenzamide 317 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-hydroxy-1- phenylpropyl)-5-methyl-N′,N′-dipropylisophthalamide 319 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-[2- (dimethylamino)ethyl]-N′-ethyl-N-(3-ethylbenzyl)-5-methylisophthalamide 321 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine-4-carboxamide 323 2-(5-acetyl-2-thienyl)-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2- hydroxybutyl]-N-(3-ethylbenzyl)acetamide 325 N¹-[(2R,3S)-3-amino-4-(3,5-dichlorophenyl)-2-hydroxybutyl]-N¹-(3- methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 327 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- N′,N′-diisopropyl-5-methylisophthalamide 329 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-[(methylsulfonyl)amino]benzamide 331 N¹-[(2R,3S)-3-amino-4-(4-chlorophenyl)-2-hydroxybutyl]-N¹-(3- methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 333 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-iodobenzyl)- 2-[4-(2-oxopyrrolidin-1-yl)phenyl]acetamide 335 N-[(2R,3S)-3-amino-4-(3-chloro-5-fluorophenyl)-2-hydroxybutyl]-3- [(dipropylamino)sulfonyl]-N-(3-methoxybenzyl)propanamide 337 N¹-[(2R,3S)-3-amino-4-(3-chloro-5-fluorophenyl)-2-hydroxybutyl]-N¹-(3- methylbutyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 339

341

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethyl-benzyl)-3-{[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}benzamide trihydrochloride 343

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-pentyl-N′,N′-dipropylisophthalamide 345 N¹-[(2R,3S)-3-amino-4-(4-fluorophenyl)-2-hydroxybutyl]-N¹-(3- methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 347 N-[(2R,3S)-3-amino-4-(3-chloro-5-fluorophenyl)-2-hydroxybutyl]-N-benzyl-5- methyl-N′,N′-dipropylisophthalamide 349 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-cyclohexyl-N′- ethyl-N-(3-ethylbenzyl)-5-methylisophthalamide 351 2-([(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]{3- [(dipropylamino)carbonyl]-5-methylbenzoyl}amino)ethyl (2,4- difluorophenyl)carbamate 353 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}-5-methylbenzamide hydrochloride 355 N¹-[(2R,3S)-3-amino-4-(3-fluoro-4-methylphenyl)-2-hydroxybutyl]-N¹-(3- methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 357 N¹-[(2R,3S)-3-amino-4-(3-bromophenyl)-2-hydroxybutyl]-N¹-(3-methylbutyl)- N³,N³-dipropylbenzene-1,3,5-tricarboxamide 359 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2,8-dimethylquinoline-3-carboxamide 361 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(6- hydroxyhexyl)-5-methyl-N′,N′-dipropylisophthalamide 363 N-[(2R,3S)-3-amino-4-(3,5 difluorophenyl)-2-hydroxybutyl]-N-[(2R)-2- hydroxypropyl]-5-methyl-N′,N′-dipropylisophthalamide 365 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(3-methoxybenzyl)-3-[(1- propylbutyl)sulfonyl]propanamide 367 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-{[(2-hydroxy-1,1-dimethylethyl)amino]sulfonyl}benzamide 369 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-(4- phenylbutyl)-N′,N′-dipropylisophthalamide 371 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-7-(1H-imidazol-1- yl)-N-(3-iodobenzyl)-5,6-dihydronaphthalene-2-carboxamide 373 3-(acetylamino)-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N- (3-ethylbenzyl)-4-methylbenzamide 375 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[2- (aminosulfonyl)ethyl]-5-methyl-N′,N′-dipropylisophthalamide 377 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[2- (ethylthio)ethy]-5-methyl-N′,N′-dipropylisophthalamide 379 N-[(2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutyl]-N-(3-methoxybenzyl)-5- methyl-N′,N′-dipropylisophthalamide 381

383

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(2-hydroxypropyl)-5-methyl-N′,N′-dipropylisophthalamide 385 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- butoxypropyl)-5-methyl-N′N′-dipropylisophthalamide 387 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-{[2-(2-hydroxyethyl)piperidin-1-yl]carbonyl}-5-methylbenzamide 389 methyl N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-{3- [(dipropylamino)carbonyl]-5-methylbenzoyl}-β-alaninate 391 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-(1-hydroxy-2-propylpentyl)benzamide 393 N¹-[(2R,3S)-3-amino-4-(3-chloro-5-fluorophenyl)-2-hydroxybutyl]-N¹-benzyl- N³,N³-dipropylbenzene-1,3,5-tricarboxamide 395 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4-[(methylsulfonyl)amino]butanamide trifluoroacetate (salt) 397 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[3-(1- benzothien-2-yl)benzyl]-5-methyl-N′,N′-propylisophthalamide 399 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(benzyloxy)-N- (3-ethylbenzyl)isoxazole-5-carboxamide 401

403 1-(3-{[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]carbonyl}-5-methylbenzoyl)-D-prolinamide 405 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 5-(1H-pyrazol-1-yl)pentanamide 407 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 1-(2-furylmethyl)-5-oxopyrrolidine-3-carboxamide 409 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-2-ethyl-N-(3- methoxybenzyl)hexanamide hydrochloride 411 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(5- hydroxypentyl)-5-methyl-N′,N′-dipropylisophthalamide 413 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3- methoxybenzyl)-N³,N³-dipropylpiperidine-1,3-dicarboxamide 415 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl[-N³,N³-diethyl-N¹- (3-methoxybenzyl)piperidine-1,3-dicarboxamide 417 N-[(2R,3S)-3-amino-2-hydroxy-4-(pentafluorophenyl)butyl]-5-bromo-N′,N′- dipropyl-N-[3-(trifluoromethyl)benzyl]isophthalamide 419 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4-[(methylsulfonyl)amino]benzamide 421

423

N-[(2R,3S)-3-amino-4-(3-bromophenyl)-2-hydroxy-butyl]-3-[(dipropylamino)sulfonyl]-N-(3-methoxy-benzyl)propanamide 425 N-[(2R,3S)-3-amino-2-hydroxy-4-(2-thienyl)butyl]-3-[(dipropylamino)sulfonyl]- N-(3-methoxybenzyl)propanamide 427 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- ethoxypropyl)-5-methyl-N′,N′-dipropylisophthalamide 429 N-[(2R,3S)-3-amino-2-hydroxy-4-(2-thienyl)butyl]-N-benzyl-5-methyl-N′,N′- dipropylisophthalamide 431

433 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-hydroxy-4-(phenylsulfonyl)butanamide hydrochloride 435 N¹-[(2R,3S)-3-amino-4-(3,5-dichlorophenyl)-2-hydroxybutyl]-N¹-(3- methylbutyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 437 N¹-{(2R,3S)-3-amino-2-hydroxy-4-[3-(trifluoromethoxy)phenyl]butyl}-N¹-(3- methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 438 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3,3- dimethylbutyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 440 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(3-bromophenyl)propyl 3- (aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 442 (1R,2S)-2-amino-3-(3-chloro-5-fluorophenyl)-1-{[(3- methylbutyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 444 get,0084 446 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(1,3- diphenylpropyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 448 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(1S)-1- (hydroxymethyl)propyl]amino}methyl)propyl 3- [(dipropylamino)carbonyl]benzoate 450 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(3S)-2-oxoazepan-3- yl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 452 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-(cyclohexylamino)-5-oxopentanoate 454 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-(3- methylphenyl)propyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 456 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(2-propylpentyl)sulfonyl]-β-alaninate trifluoroacetate 458

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethyl-benzyl)amino]methyl}propyl3-(1,3-thiazol-2-yl)benzoatedihydrochloride 460

(1R,2S)-2-amino-3-(2-furyl)-1-{[(3-methoxybenzyl)amino]methyl}propyl 3-[(dipropyl-amino)carbonyl]-5-methylbenzoate 462 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-[({3- [methyl(phenyl)amino]propyl}amino)methyl]propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 464 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-(4- methylphenyl)propyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 466 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-oxo-1-(2-thienylmethyl)pyrrolidine-3- carboxylate 468 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-[(butylthio)methyl]-5-methyl-2-furoate 470 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[(2-hydroxyethyl)amino]sulfonyl}benzoate 472 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[3-(trifluoromethyl)benzoyl]glycinate 474 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- methylcyclohexyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 476 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(2-oxo-1,3-oxazolidin-3-yl)benzoate 478 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(1H-pyrrol-1-yl)benzoate 480 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(6-methoxy-1,2,3,4- tetrahydronaphthalen-1-yl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 482 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 1,3,4,5-tetrahydrothiopyrano[4,3-b]indole-8- carboxylate 484 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-oxo-4-{[2- (trifluoromethyl)phenyl]amino}butanoate 486 (1R,2S)-2-amino-3-(3-bromophenyl)-1-{[(3-methylbutyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 488 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4,5-dimethyl-2-(1H-pyrrol-1-yl)thiophene-3- carboxylate 490 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(2,3- dihydroxypropyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 492 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(2S)-2- hydroxypropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 494 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(1R)-1- methylpropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 496 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-chloro-4-(methylsulfonyl)benzoate 498 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(2- hydroxyethyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 500 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-(3- methoxyphenyl)propyl 3-[(dipropylamino)sulfonyl]propanoate 502 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3- {methyl[(trifluoromethyl)sulfonyl]amino}benzoate hydrochloride 504 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-hydroxy-6-(1-hydroxy-2,2- dimethylpropyl)pyridine-2-carboxylate 506 (1R,2S)-2-amino-1-{[(1,3-dicyclohexylpropyl)amino]methyl}-3-(3,5- difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 508 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2,2′-bithiophene-5-carboxylate 510 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(1H-imidazol-1-yl)butanoate 512 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2,3-dihydroxy-4-[(4-methoxyphenyl)amino]- 4-oxobutanoate 514 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(4-hydroxyphenyl)propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 516 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-[3- (trifluoromethyl)phenyl]propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 518 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(2-thienyl)propyl 3- (aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 520 (1R,2S)-2-amino-1-({[2-(aminocarbonyl)-1H-indol-6-yl]amino}methyl)-3-(3,5- difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 522 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(3-bromophenyl)propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 524 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[4-(trifluoromethyl)benzoyl]glycinate 526 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-(1-oxo-1,3-dihydro-2H-isoindol-2- yl)butanoate 528 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(3,4-dichlorobenzoyl)glycinate 530 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-chloro-4-(methylsulfonyl)thiophene-2- carboxylate 532 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(1- ethylpropyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 534 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-[({[(5R)-3-ethyl-2-oxo-1,3- oxazolidin-5-yl]methyl}amino)methyl]propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 536 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-methyl-7-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine-2-carboxylate 538 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl N- [(methylthio)acetyl]-3-[(1-propylbutyl)sulfonyl]alaninate hydrochloride 540 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(2,3- dimethylcyclohexyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 542 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4,5-dimethoxy-1-benzothiophene-2- carboxylate 544 (1R,2S)-2-amino-3-[3-fluoro-5-(trifluoromethyl)phenyl]-1-{[(3- methylbutyl)amino]methyl}propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 546 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-[({[(5S)-3-ethyl-2-oxo-1,3- oxazolidin-5-yl]methyl}amino)methyl]propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 548 (1R,2S)-2-amino-3-(1,3-benzodioxol-5-yl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 550 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(3,5-dioxo-1,2,4-triazolidin-4-yl)benzoate 552 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 2- hydroxy-3-[(3-methoxyphenyl)sulfonyl]propanoate hydrochloride 554

556

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(2-methylcyclohexyl)amino]methyl}propyl 3-[(dipropyl-amino)carbonyl]-5-methylbenzoate 558

(1R,2S)-2-amino-1-{[(2-{4-[(3-chlorobenzyl)oxy]phenyl}ethyl)amino]methyl}-3-(3,5-difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 560 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-hydroxy-4-oxo-4-(3-thienyl)butanoate 562 (1R,2S)-2-amino-3-[3-(benzyloxy)-5-fluorophenyl]-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 564 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-hydroxy-4-oxo-4-[3- (trifluoromethyl)phenyl]butanoate 566 (1R,2S)-2-amino-1-{[(3-methylbutyl)amino]methyl}-3-[3- (trifluoromethoxy)phenyl]propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 568 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(hydroxymethyl)-3- (methylthio)propyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 570 (1R,2S)-2-amino-3-(3,5-difluorophenyl-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-(1H-1,2,3,-benzotriazol-1-yl)hexanoate 572 (1R,2S)-2-amino-3-(3-fluoro-4-methylphenyl-1-{[(3- methylbutyl)amino]methyl}propyl 3-(aminocarbonyl-5- [(dipropylamino)carbonyl]benzoate 574 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)- 2-{[(1-propylbutyl)sulfonyl]methyl}propanoate 576 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4- {[(trifluoromethyl)sulfonyl]amino}butanoate trifluoroacetate 578 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol 2-yl)acetate 580 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- hydroxypropyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 582 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1- (hydroxymethyl)propyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 584 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(3,5-dichlorophenyl)propyl 3- (aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 586 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 3-{[(2- hydroxyethyl)(propyl)amino]sulfonyl}propanoate hydrochloride 588 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-(benzylthio)nicotinate 590 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 1H-pyrazole-5-carboxylate 592 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 6-chloro-3-methyl-2-oxo-2,3-dihydro-1,3- benzoxazole-5-carboxylate 594 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 1H-benzimidazole-2-carboxylate 596 (1R,2S)-2-amino-3-cyclohexyl-1-{[(3-methoxybenzyl)amino]methyl}propyl 3- (aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 598 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 6-hydroxy-4,7-dimethoxy-1-benzofuran-5- carboxylate 600 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(4- methylcyclohexyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 602 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl [1,2,4]triazolo[4,3-a]pyridine-6-carboxylate 604 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-hydroxy-4-oxo-4-(2-thienyl)butanoate 606 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(3,5-dichlorophenyl)propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 608 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(2-hydroxy-5-methylphenyl)-4- oxobutanoate 610 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-phenoxybenzoate 612 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-[(aminocarbonyl)amino]benzoate 614 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(1S)-1-(hydroxymethyl)-3- (methylthio)propyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 616 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 7-hydroxy-4-oxochromane-2-carboxylate 618 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(1S)-1-(hydroxymethyl)-3- methylbutyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 620 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(1R)-1- (hydroxymethyl)propyl]amino}methyl)propyl 3- [(dipropylamino)carbonyl]benzoate 622 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(1-methyl-3- phenylpropyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 439 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3,3- dimethylbutyl)-5-methyl-N′,N′-dipropylisophthalamide 441 N¹-[(2R,3S)-3-amino-4-(3-bromophenyl)-2-hydroxybutyl]-N¹-benzyl-N³,N³- dipropylbenzene-1,3,5-tricarboxamide 443 N-[(2R,3S)-3-amino-4-(3-chloro-5-fluorophenyl)-2-hydroxybutyl]-5-methyl-N- (3-methylbutyl)-N′,N′-dipropylisophthalamide 445

447

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxy-butyl]-N-(1,3-diphenylpropyl)-5-methyl-N′,N′-dipropylisophthalamide 449

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxy-butyl]-N-[(1S)-1-(hydroxy-methyl)propyl]-N′,N′-dipropylisophthalamide 451 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-[(3S)- 2-oxoazepan-3-yl]-N′,N′-dipropylisophthalamide 453 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-cyclohexyl-N- (3-ethylbenzyl)pentanediamide 455 N¹-[(2R,3S)-3-amino-2-hydroxy-4-(3-methylphenyl)butyl]N¹-(3- methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 457 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3- ethylbenzyl)-N³-[(2-propylpentyl)sulfonyl]-β-alaninamide trifluoroacetate (salt) 459 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-(1,3-thiazol-2-yl)benzamide dihydrochloride 461 N-[(2R,3S)-3-amino-4-(2-furyl)-2-hydroxybutyl]-N-(3-methoxybenzyl)-5- methyl-N′,N′-dipropylisophthalamide 463 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-{3- [methyl(phenyl)amino]propyl}-N′,N′-dipropylisophthalamide 465 N¹-[(2R,3S)-3-amino-2-hydroxy-4-(4-methylphenyl)butyl]-N¹-(3- methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 467 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 5-oxo-1-(2-thienylmethyl)pyrrolidine-3-carboxamide 469 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4- [(butylthio)methyl]-N-(3-ethylbenzyl)-5-methyl-2-furamide 471 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-{[(2-hydroxyethyl)amino]sulfonyl}benzamide 473

475

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxy-butyl]-5-methyl-N-(3-methyl-cyclohexyl)-N′,N′-dipropylisophthalamide 477 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4-(2-oxo-1,3-oxazolidin-3-yl)benzamide 479 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4-(1H-pyrrol-1-yl)benzamide 481 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(6-methoxy- 1,2,3,4-tetrahydronaphthalen-1-yl)-5-methyl-N′,N′-dipropylisophthalamide 483 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 1,3,4,5-tetrahydrothiopyrano[4,3-b]indole-8-carboxamide 485 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- N′-[2-(trifluoromethyl)phenyl]succinamide 487 N-[(2R,3S)-3-amino-4-(3-bromophenyl)-2-hydroxybutyl]-5-methyl-N-(3- methylbutyl)-N′,N′-dipropylisophthalamide 489 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4,5-dimethyl-2-(1H-pyrrol-1-yl)thiophene-3-carboxamide 491 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(2,3- dihydroxypropyl)-5-methyl-N′,N′-dipropylisophthalamide 493 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[(2S)-2- hydroxypropyl]-5-methyl-N′,N′-dipropylisophthalamide 495 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-[(1R)- 1-methylpropyl]-N′,N′-dipropylisophthalamide 497 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-chloro-N-(3- ethylbenzyl)-4-(methylsulfonyl)benzamide 499 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(2- hydroxyethyl)-5-methyl-N′,N′-dipropylisophthalamide 501 N-[(2R,3S)-3-amino-2-hydroxy-4-(3-methoxyphenyl)butyl]-3- [(dipropylamino)sulfonyl]-N-(3-methoxybenzyl)propanamide 503 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-{methyl[(trifluoromethyl)sulfonyl]amino}benzamide hydrochloride 505 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-hydroxy-6-(1-hydroxy-2,2-dimethylpropyl)pyridine-2-carboxamide 507 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(1,3- dicyclohexylpropyl)-5-methyl-N′,N′-dipropylisophthalamide 509 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2,2′-bithiophene-5-carboxamide 511 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4-(1H-imidazol-1-yl)butanamide 513 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2,3-dihydroxy-N′-(4-methoxyphenyl)succinamide 515 N-[(2R,3S)-3-amino-2-hydroxy-4-(4-hydroxyphenyl)butyl]-N-benzyl-5-methyl- N′,N′-dipropylisophthalamide 517 N¹-{(2R,3S)-3-amino-2-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl}-N¹-(3- methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 519 N¹-[(2R,3S)-3-amino-2-hydroxy-4-(2-thienyl)butyl]-N¹-benzyl-N³,N³- dipropylbenzene-1,3,5-tricarboxamide 521 N-[2-(aminocarbonyl)-1H-indol-6-yl]-N-[(2R,3S)-3-amino-4-(3,5- difluorophenyl)-2-hydroxybutyl]-5-methyl-N′,N′-dipropylisophthalamide 523 N-[(2R,3S)-3-amino-4-(3-bromophenyl)-2-hydroxybutyl]-N-benzyl-5-methyl- N′,N′-dipropylisophthalamide 525

527

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxy-butyl]-N-(3-ethylbenzyl)-2-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)butanamide 529

531 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-chloro-N-(3- ethylbenzyl)-4-(methylsulfonyl)thiophene-2-carboxamide 533 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(1-ethylpropyl)- 5-methyl-N′,N′-dipropylisophthalamide 535 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-{[(5R)-3-ethyl-2- oxo-1,3-oxazolidin-5-yl]methyl}-5-methyl-N′,N′-dipropylisophthalamide 537 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 5-methyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide 539 N¹-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N¹-(3-methoxybenzyl)-N²- [(methylthio)acetyl]-3-[(1-propylbutyl)sulfonyl]alaninamide hydrochloride 541 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(2,3- dimethylcyclohexyl)-5-methyl-N′,N′-dipropylisophthalamide 543 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4,5-dimethoxy-1-benzothiophene-2-carboxamide 545 N-{(2R,3S)-3-amino-4-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxybutyl}- N¹-(3-methylbutyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 547 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-{[(5S)-3-ethyl-2- oxo-1,3-oxazolidin-5-yl]methyl}-5-methyl-N′,N′-dipropylisophthalamide 549 N¹-[(2R,3S)-3-amino-4-(1,3-benzodioxol-5-yl)-2-hydroxybutyl]-N¹-(3- methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 551 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-(3,5-dioxo-1,2,4- triazolidin-4-yl)-N-(3-ethylbenzyl)benzamide 553 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-2-hydroxy-N-(3- methoxybenzyl)-3-[(3-methoxyphenyl)sulfonyl]propanamide hydrochloride 555

557 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-(2- methylcyclohexyl)-N′,N′-dipropylisophthalamide 559 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(2-{4-[(3- chlorobenzyl)oxy]phenyl}ethyl)-5-methyl-N′,N′-dipropylisophthalamide 561 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-hydroxy-4-oxo-4-(3-thienyl)butanamide 563 N¹-{(2R,3S)-3-amino-4-[3-(benzyloxy)-5-fluorophenyl]-2-hydroxybutyl}-N¹-(3- methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 565 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-hydroxy-4-oxo-4-[3-(trifluoromethyl)phenyl]butanamide 567 N¹-{(2R,3S)-3-amino-2-hydroxy-4-[3-(trifluoromethoxy)phenyl]butyl}-N¹-(3- methylbutyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 569 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[1- (hydroxymethyl)-3-(methylthio)propyl]-5-methyl-N′,N′-dipropylisophthalamide 571 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-(1H-1,2,3- benzotriazol-1-yl)-N-(3-ethylbenzyl)hexanamide 573 N¹-[(2R,3S)-3-amino-4-(3-fluoro-4-methylphenyl)-2-hydroxybutyl]-N¹-(3- methylbutyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 575 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(4,4-dimethyl- 2,5-dioxoimidazolidin-1-yl)-N-(3-ethylbenzyl)-2-{[(1- propylbutyl)sulfonyl]methyl}propanamide 577 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4-{[(trifluoromethyl)sulfonyl]amino}butanamide trifluoroacetate (salt) 579 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-(5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetamide 581 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- hydroxypropyl)-5-methyl-N′,N′-dipropylisophthalamide 583 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[1- (hydroxymethyl)propyl]-5-methyl-N′,N′-dipropylisophthalamide 585 N¹-[(2R,3S)-3-amino-4-(3,5-dichlorophenyl)-2-hydroxybutyl]-N¹-benzyl-N³,N³- dipropylbenzene-1,3,5-tricarboxamide 587 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3-{[(2- hydroxyethyl)(propyl)amino]sulfonyl}-N-(3-methoxybenzyl)propanamide hydrochloride 589 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-(benzylthio)-N- (3-ethylbenzyl)nicotinamide 591 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 1H-pyrazole-5-carboxamide 593 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-6-chloro-N-(3- ethylbenzyl)-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carboxamide 595 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 1H-benzimidazole-2-carboxamide 597 N¹-[(2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutyl]-N¹-(3-methoxybenzyl)- N³,N³-dipropylbenzene-1,3,5-tricarboxamide 599 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 6-hydroxy-4,7-dimethoxy-1-benzofuran-5-carboxamide 601 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-(4- methylcyclohexyl)-N′,N′-dipropylisophthalamide 603 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- ethylbenzyl)[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide 605 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-hydroxy-4-oxo-4-(2-thienyl)butanamide 607 N-[(2R,3S)-3-amino-4-(3,5-dichlorophenyl)-2-hydroxybutyl]-N-benzyl-5- methyl-N′,N′-dipropylisophthalamide 609 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4-(2-hydroxy-5-methylphenyl)-4-oxobutanamide 611 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-phenoxybenzamide 613 4-[(aminocarbonyl)amino]-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2- hydroxybutyl]-N-(3-ethylbenzyl)benzamide 615 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[(1S)-1- (hydroxymethyl)-3-(methylthio)propyl]-5-methyl-N′,N′-dipropylisophthalamide 617 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 7-hydroxy-4-oxochromane-2-carboxamide 619 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[(1S-1- (hydroxymethyl)-3-methylbutyl]-5-methyl-N′,N′-dipropylisophthalamide 621 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[(1R)-1- (hydroxymethyl)propyl]-N′,N′-dipropylisophthalamide 623 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-(1- methyl-3-phenylpropyl)-N′,N′-dipropylisophthalamide 624 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-(2,3-dihydro-1-benzofuran-5-yl)-1,3- thiazole-4-carboxylate 626 (1R,2S)-2-amino-3-[3-(benzyloxy)phenyl]-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 628 (1R,2S)-2-amino-3-(4-chlorophenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)sulfony]propanoate 630 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-oxo-3-(pentylamino)propanoate 632 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzy)amino]methyl}propyl 3-(trifluoromethoxy)benzoate 634 (1R,2S)-2-amino-3-(3-fluoro-4-methylphenyl-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)sulfonyl]propanoate 636 (1R,2S)-2-amino-3-(3-chloro-5-fluorophenyl)-1-{[(3- methylbutyl)amino]methyl}propyl 3-[(dipropylamino)sufonyl]propanoate 638 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)- 2-{[(1-propylbutyl)sulfonyl]methyl}propanoate 640 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-{[4-(acetylamino)phenyl]amino}-4- oxobutanoate 642 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(1-cyanoethyl)benzoate 644 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-oxo-4-[(5-phenyl-1,3,4-thiadiazol-2- yl)amino]butanoate 646 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-[3- (trifluoromethoxy)phenyl]propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 648 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[2-(2-oxo-2-pyrrolidin-1- ylethoxy)phenyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 650 (1R,2S)-2-amino-3-(4-chlorophenyl)-1-{[(3-methylbutyl)amino]methyl}propyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 652 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (1,1-dioxidotetrahydro-2-thienyl)acetate 654 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(4-chlorophenyl)propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 656 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-hex-1-yn-1-ylnicotinate 658 (1R,2S)-2-amino-3-(3-bromophenyl)-1-{[(3-methylbutyl)amino]methyl}propyl 3-[(dipropylamino)sulfonyl]propanoate 660 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-methoxyisoxazole-5-carboxylate 662 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2,3-dimethyl-1H-indole-7-carboxylate 664 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(3-chlorophenyl)-2-hydroxy-4- oxobutanoate 666 (1R,2S)-2-amino-3-(3-fluoro-4-methoxyphenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 668 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (1-methyl-1H-indol-3-yl)(oxo)acetate 670 (1R,2S)-2-amino-3-(3-fluoro-4-methylphenyl)-1-{[(3- methylbutyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 672 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-(4- methylphenyl)propyl 3-[(dipropylamino)sulfonyl]propanoate 674 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(3-fluoro-4-methylphenyl)propyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 676 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl [5-(4-methylphenyl)-2H-tetrazol-2-yl]acetate 678 (1R,2S)-2-amino-3-(3,5-dichlorophenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)sulfonyl]propanoate 680 (1R,2S)-2-amino-1-{[(3-methylbutyl)amino]methyl}-3-(2-thienyl)propyl 3- (aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 682 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-methyl-3-phenylisoxazole-4-carboxylate 684 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(4-fluorophenyl)propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 686 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(methylsulfonyl)acetyl]-N-pentylglycinate 688 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(4-methoxybenzoyl)glycinate 690 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(2,6-difluorobenzoyl)glycinate 692 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(1H-indol-3-yl)-4-oxobutanoate 694 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-[(5-benzyl-1,3,4-thiadiazol-2-yl)amino]-4- oxobutanoate 696 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(3-fluoro-4-methoxyphenyl)-4- oxobutanoate 698 ethyl 4-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-({3- [(dipropylamino)carbonyl]-5-methylbenzoyl}oxy)butyl]amino}piperidine-1- carboxylate 700 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(2-fluorobenzoyl)-1H-pyrrole-2-carboxylate 702 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(4-chlorophenyl)propyl 3- (aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 704 (1R,2S)-2-amino-1-{[(3-methylbutyl)amino]methyl}-3-[3- (trifluoromethyl)phenyl]propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 706 (1R,2S)-2-amino-3-(4-hydroxyphenyl)-1-{[(3-methylbutyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 708 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (4-morpholin-4-ylphenyl)acetate 710 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-[3- (trifluoromethoxy)phenyl]propyl 3-[(dipropylamino)sulfonyl]propanoate 712 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-[benzyl(1-cyclopropylethyl)amino]-4- oxobutanoate 714 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-(2,5-dimethylbenzoyl)-5- methylbenzoate 716 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-[(2-methoxy-5-methylphenyl)amino]-4- oxobutanoate 718 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (3-hydroxyphenyl)acetate 720 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-[hydroxy(2-methylphenyl)methyl]-5- methylbenzoate 722 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-(ethylthio)nicotinate 724 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-[4-(2-furoyl)piperazin-1-yl]-4-oxobutanoate 726 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(3-fluoro-4-methylphenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 728 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-oxoisoindoline-1-carboxylate 730 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(ethylthio)benzoate 732 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl thieno[2,3-b]quinoline-2-carboxylate 734 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(4-methyl-1,3-oxazol-2-yl)benzoate hydrochloride 736 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(4-fluorophenyl)propyl 3- (aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 738 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-[2-furoyl(methyl)amino]benzoate 740 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-hydroxy-4-(3-methoxyphenyl)-4- oxobutanoate 742 (1R,2S)-2-amino-1-[(cycloheptylamino)methyl]-3-(3,5-difluorophenyl)propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 744 (1R,2S)-2-amino-1-{[(3-methylbutyl)amino]methyl}-3-(4-methylphenyl)propyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 746 (1R,2S)-2-amino-3-(3-fluoro-5-hydroxyphenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)sulfonyl]propanoate hydrochloride 748 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-hydroxy-1H-indole-2-carboxylate 750 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2,2-dimethylchromane-8-carboxylate 752 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 6-benzylpyrazine-2-carboxylate 4-oxide 754 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl {2- [(dipropylamino)sulfonyl]ethyl}carbamate 756 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(hydroxymethyl)-2- methylpropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 758 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(3-chloro-5-fluorophenyl)propyl 3- [(dipropylamino)sulfonyl]propanoate 760 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(4-methoxyphenyl)-4-oxobutanoate 762 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(4-hydroxyphenyl)propyl 3- (aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 764 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-methyl-4-oxo-3,4-dihydrophthalazine-1- carboxylate 766 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3,4-dihydro-2H-1,5-benzodioxepine-7- carboxylate 768 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl [4-(2,5-dioxopyrrolidin-1-yl)phenoxy]acetate 770 (1R,2S)-2-amino-3-(2-furyl)-1-{[(3-methoxybenzyl)amino]methyl}propyl 3- (aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 772 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3- d]pyrimidine-6-carboxylate 774 (1R,2S)-2-amino-3-(1,3-benzodioxol-5-yl)-1-{[(3- methylbutyl)amino]methyl}propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 776

778

(1R,2S)-2-amino-3-(3-chloro-5-fluorophenyl)-1-{[(3-methoxybenzyl)amino]methyl}propyl 5-(dipropylamino)-5-oxopentanoate 780

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 6-fluoro-2-hydroxy-quinoline-4-carboxylate 782

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-oxo-4-(2-thienyl)butanoate 784

786 (1R,2R)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-(phenylthio)propyl 3- (aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 788 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(1R)-1-(hydroxymethyl)-2- methylpropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 790 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(1R,2S)-1-(hydroxymethyl)-2- methylbutyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 792 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-(phenoxymethyl)benzoate 794 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-[(2,4-difluorophenyl)amino]-5- oxopentanoate 796 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-[(4,6-dimethylpyrimidin-2-yl)amino]-5- oxopentanoate 798 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-(3-methoxybenzoyl)-5-methylbenzoate 800 (1R,2S)-2-amino-3-[3-(benzyloxy)phenyl]-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 802 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(3,4-dichlorophenyl)-4-oxobutanoate 804 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-[4- (methoxycarbonyl)phenyl]propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 806 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-[(4-acetylphenyl)amino]-5-oxopentanoate 808 (1R,2S)-2-amino-3-[4-(benzyloxy)phenyl]-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 810 (1R,2R)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-(phenylthio)propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 812 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-({2- [(methylamino)carbonyl]phenyl}thio)propanoate 814 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 3-[(1- propylbutyl)thio]propanoate hydrochloride 816 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-[(4-ethoxyphenyl)amino]-4-oxobutanoate 818 (1R,2S)-2-amino-3-[3-(benzyloxy)-5-fluorophenyl]-1-{[(3- methylbutyl)amino]methyl}propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 820 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[2-({[(3- methoxyphenyl)amino]carbonyl}oxy)ethyl]amino}methyl)propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 625 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-(2,3-dihydro-1- benzofuran-5-yl)-N-(3-ethylbenzyl)-1,3-thiazole-4-carboxamide 627 N-{(2R,3-S)-3-amino-4-[3-(benzyloxy)phenyl]-2-hydroxybutyl}-N-(3- methoxybenzyl)-5-methyl-N′,N′-dipropylisophthalamide 629 N-[(2R,3S)-3-amino-4-(4-chlorophenyl)-2-hydroxybutyl]-3- [(dipropylamino)sulfonyl]-N-(3-methoxybenzyl)propanamide 631 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- N′-pentylmalonamide 633 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-(trifluoromethoxy)benzamide 635 N-[(2R,3S)-3-amino-4-(3-fluoro-4-methylphenyl)-2-hydroxybutyl]-3- [(dipropylamino)sulfonyl]-N-(3-methoxybenzyl)propanamide 637 N-[(2R,3S)-3-amino-4-(3-chloro-5-fluorophenyl)-2-hydroxybutyl]-3- [(dipropylamino)sulfonyl]-N-(3-methylbutyl)propanamide 639 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(4,4-dimethyl- 2,5-dioxoimidazolidin-1-yl)-N-(3-ethylbenzyl)-2-{[(1- propylbutyl)sulfonyl]methyl}propanamide 641 N′-[4-(acetylamino)phenyl]-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2- hydroxybutyl]-N-(3-ethylbenzyl)succinamide 643 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(1-cyanoethyl)- N-(3-ethylbenzyl)benzamide 645 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- N′-(5-phenyl-1,3,4-thiadiazol-2-yl)succinamide 647 N¹-{(2R,3S)-3-amino-2-hydroxy-4-[3-(trifluoromethoxy)phenyl]butyl}-N¹- benzyl-N³,N³-diproplbenzene-1,3,5-tricarboxamide 649 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-[2-(2- oxo-2-pyrrolidin-1-ylethoxy)phenyl]-N′,N′-dipropylisophthalamide 651 N¹-[(2R,3S)-3-amino-4-(4-chlorophenyl)-2-hydroxybutyl]-N¹-(3-methylbutyl)- N³,N³-dipropylbenzene-1,3,5-tricarboxamide 653 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-(1,1- dioxidotetrahydro-2-thienyl)-N-(3-ethylbenzyl)acetamide 655 N-[(2R,3S)-3-amino-4-(4-chlorophenyl)-2-hydroxybutyl]-N-benzyl-5-methyl- N′,N′-dipropylisophthalamide 657 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 5-hex-1-yn-1-ylnicotinamide 659 N-[(2R,3S)-3-amino-4-(3-bromophenyl)-2-hydroxybutyl]-3- [(dipropylamino)sulfonyl]-N-(3-methylbutyl)propanamide 661 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-methoxyisoxazole-5-carboxamide 663 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2,3-dimethyl-1H-indole-7-carboxamide 665 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-(3-chlorophenyl)- N-(3-ethylbenzyl)-2-hydroxy-4-oxobutanamide 667 N¹-[(2R,3S)-3-amino-4-(3-fluoro-4-methoxyphenyl)-2-hydroxybutyl]-N¹-(3- methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 669 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-(1-methyl-1H-indol-3-yl)-2-oxoacetamide 671 N-[(2R,3S)-3-amino-4-(3-fluoro-4-methylphenyl)-2-hydroxybutyl]-5-methyl-N- (3-methylbutyl)-N′,N′-dipropylisophthalamide 673 N-[(2R,3S)-3-amino-2-hydroxy-4-(4-methylphenyl)butyl]-3- [(dipropylamino)sulfonyl]-N-(3-methoxybenzyl)propanamide 675 N¹-[(2R,3S)-3-amino-4-(3-fluoro-4-methylphenyl)-2-hydroxybutyl]-N¹-benzyl- N³,N³-dipropylbenzene-1,3,5-tricarboxamide 677 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-[5-(4-methylphenyl)-2H-tetrazol-2-yl]acetamide 679 N-[(2R,3S)-3-amino-4-(3,5-dichlorophenyl)-2-hydroxybutyl]-3- [(dipropylamino)sulfonyl]-N-(3-methoxybenzyl)propanamide 681 N¹-[(2R,3S)-3-amino-2-hydroxy-4-(2-thienyl)butyl]-N¹-(3-methylbutyl)-N³,N³- dipropylbenzene-1,3,5-tricarboxamide 683 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 5-methyl-3-phenylisoxazole-4-carboxamide 685 N-[(2R,3S)-3-amino-4-(4-fluorophenyl)-2-hydroxybutyl]-N-benzyl-5-methyl- N′,N′-dipropylisophthalamide 687 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3- ethylbenzyl)-N²-[(methylsulfonyl)acetyl]-N²-pentylglycinamide 689

691

693

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-4-(1H-indol-3-yl)-4-oxobutanamide 695 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-(5-benzyl-1,3,4- thiadiazol-2-yl)-N-(3-ethylbenzyl)succinamide 697 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4-(3-fluoro-4-methoxyphenyl)-4-oxobutanamide 699 ethyl 4-([(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]{3- [(dipropylamino)carbonyl]-5-methylbenzoyl}amino)piperidine-1-carboxylate 701 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4-(2-fluorobenzoyl)-1H-pyrrole-2-carboxamide 703 N¹-[(2R,3S)-3-amino-4-(4-chlorophenyl)-2-hydroxybutyl]-N¹-benzyl-N³,N³- dipropylbenzene-1,3,5-tricarboxamide 705 N¹-{(2R,3S)-3-amino-2-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl}-N¹-(3- methylbutyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 707 N-[(2R,3S)-3-amino-2-hydroxy-4-(4-hydroxyphenyl)butyl]-5-methyl-N-(3- methylbutyl)-N′,N′-dipropylisophthalamide 709 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-(4-morpholin-4-ylphenyl)acetamide 711 N-{(2R,3S)-3-amino-2-hydroxy-4-[3-(trifluoromethoxy)phenyl]butyl}-3- [(dipropylamino)sulfonyl]-N-(3-methoxybenzyl)propanamide 713 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-benzyl-N′-(1- cyclopropylethyl)-N-(3-ethylbenzyl)succinamide 715 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(2,5- dimethylbenzoyl)-N-(3-methoxybenzyl)-5-methylbenzamide 717 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- N′-(2-methoxy-5-methylphenyl)succinamide 719 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-(3-hydroxyphenyl)acetamide 721 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-[hydroxy(2- methylphenyl)methyl]-N-(3-methoxybenzyl)-5-methylbenzamide 723 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 5-(ethylthio)nicotinamide 725 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4-[4-(2-furoyl)piperazin-1-yl]-4-oxobutanamide 727 N-[(2R,3S)-3-amino-4-(3-fluoro-4-methylphenyl)-2-hydroxybutyl]-N-benzyl-5- methyl-N′,N′-dipropylisophthalamide 729 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-oxoisoindoline-1-carboxamide 731 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-(ethylthio)benzamide 733 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- ethylbenzyl)thieno[2,3-b]quinoline-2-carboxamide 735 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-(4-methyl-1,3-oxazol-2-yl)benzamide hydrochloride 737 N¹-[(2R,3S)-3-amino-4-(4-fluorophenyl)-2-hydroxybutyl]-N¹-benzyl-N³,N³- dipropylbenzene-1,3,5-tricarboxamide 739 N-(2-{[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]carbonyl}phenyl)-N-methyl-2-furamide 741 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-hydroxy-4-(3-methoxyphenyl)-4-oxobutanamide 743 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-cycloheptyl-5- methyl-N′,N′-dipropylisophthalamide 745 N¹-[(2R,3S)-3-amino-2-hydroxy-4-(4-methylphenyl)butyl]-N¹-(3-methylbutyl)- N³,N³-dipropylbenzene-1,3,5-tricarboxamide 747 N-[(2R,3S)-3-amino-4-(3-fluoro-5-hydroxyphenyl)-2-hydroxybutyl]-3- [(dipropylamino)sulfonyl]-N-(3-methoxybenzyl)propanamide hydrochloride 749 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 5-hydroxy-1H-indole-2-carboxamide 751 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2,2-dimethylchromane-8-carboxamide 753 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-6-benzyl-N-(3- ethylbenzyl)pyrazine-2-carboxamide 4-oxide 755 2-({[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- methoxybenzyl)amino]carbonyl}amino)-N,N-dipropylethanesulfonamide 757 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[(1R)-1- (hydroxymethyl)-2-methylpropyl]-5-methyl-N′,N′-dipropylisophthalamide 759 N-[(2R,3S)-3-amino-4-(3-chloro-5-fluorophenyl)-2-hydroxybutyl]-N-benzyl-3- [(dipropylamino)sulfonyl]propanamide 761 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4-(4-methoxyphenyl)-4-oxobutanamide 763 N¹-[(2R,3S)-3-amino-2-hydroxy-4-(4-hydroxyphenyl)butyl]-N¹-benzyl-N³,N³- dipropylbenzene-1,3,5-tricarboxamide 765 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-methyl-4-oxo-3,4-dihydrophthalazine-1-carboxamide 767 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3,4-dihydro-2H-1,5-benzodioxepine-7-carboxamide 769 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-[4-(2,5- dioxopyrrolidin-1-yl)phenoxy]-N-(3-ethylbenzyl)acetamide 771 N¹-[(2R,3S)-3-amino-4-(2-furyl)-2-hydroxybutyl]-N¹-(3-methoxybenzyl)-N³,N³- dipropylbenzene-1,3,5-tricarboxamide 773 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxamide 775 N¹-[(2R,3S)-3-amino-4-(1,3-benzodioxol-5-yl)-2-hydroxybutyl]-N¹-(3- methylbutyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 777

779 N-[(2R,3S)-3-amino-4-(3-chloro-5-fluorophenyl)-2-hydroxybutyl]-N-(3- methoxybenzyl)-N′,N′-dipropylpentanediamide 781 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyly)- 6-fluoro-2-hydroxyquinoline-4-carboxamide 783 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4-oxo-4-(2-thienyl)butanamide 785 N³-{[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- methoxybenzyl)amino]carbonyl}-N¹,N¹-dipropyl-β-alaninamide 787 N¹-[(2R,3R)-3-amino-2-hydroxy-4-(phenylthio)butyl]-N¹-(3-methoxybenzyl)- N³,N³-dipropylbenzene-1,3,5-tricarboxamide 789 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[(1R)-1- (hydroxymethyl)-2-methylpropyl]-5-methyl-N′,N′-dipropylisophthaIamide 791 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[(1R,2S)-1- (hydroxymethyl)-2-methylbutyl]-5-methyl-N′,N′-dipropylisophthalamide 793 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-(phenoxymethyl)benzamide 795 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-(2,4- difluorophenyl)-N-(3-ethylbenzyl)pentanediamide 797 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-(4,6- dimethylpyrimidin-2-yl)-N-(3-ethylbenzyl)pentanediamide 799 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(3- methoxybenzoyl)-N-(3-methoxybenzyl)-5-methylbenzamide 801 N¹-{(2R,3S)-3-amino-4-[3-(benzyloxy)phenyl]-2-hydroxybutyl}-N¹-(3- methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 803 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-(3,4- dichlorophenyl)-N-(3-ethylbenzyl)-4-oxobutanamide 805 methyl 4-{(2S,3R)-2-amino-4-[{3-[(dipropylamino)carbonyl]-5- methlbenzoyl}(3-methoxybenzyl)amino]-3-hydroxybutyl}benzoate 807 N′-(4-acetylphenyl)-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2- hydroxybutyl]-N-(3-ethylbenzyl)pentanediamide 809 N-{(2R,3S)-3-amino-4-[4-(benzyloxy)phenyl]-2-hydroxybutyl}-N-(3- methoxybenzyl)-5-methyl-N′,N′-dipropylisophthalamide 811 N-[(2R,3R)-3-amino-2-hydroxy-4-(phenylthio)butyl]-N-(3-methoxybenzyl)-5- methyl-N′,N′-dipropylisophthalamide 813 2-({3-[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]-3-oxopropyl}thio)-N-methylbenzamide 815 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(3-methoxybenzyl)-3-[(1- propylbutyl)thio]propanamide hydrochloride 817 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-(4- ethoxyphenyl)-N-(3-ethylbenzyl)succinamide 819 N¹-{(2R,3S)-3-amino-4-[3-(benzyloxy)-5-fluorophenyl]-2-hydroxybutyl-N¹-(3- methylbutyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 821 2-([(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]{3- [(dipropylamino)carbonyl]-5-methylbenzoyl}amino)ethyl (3- methoxyphenyl)carbamate 822 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(benzyloxy)benzoate 824 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(1S)-2-hydroxy-1- methylethyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 826 (1R,2S)-2-amino-3-(pentafluorophenyl)-1-({[3- (trifluoromethyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 828 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(4-hydroxyphenyl)-4-oxobutanoate 830 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-[3- (trifluoromethyl)phenyl]propyl 3-[(dipropylamino)sulfonyl]propanoate 832 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(piperidin-3-ylsulfonyl)benzoate dihydrochloride 834 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 6-chloro-4-hydroxyquinoline-2-carboxylate 836 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-(2-thienyl)propyl 5- (dipropylamino)-5-oxopentanoate 838 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-4-methylpentyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 840 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (6-oxo-3-phenylpyridazin-1(6H)-yl)acetate 842 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{4- [(methylsulfonyl)amino]phenyl}propanoate 844 (1R,2S)-2-amino-3-(4-fluoro-3-methylphenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 846 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(4-methylphenyl)propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 848 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- iodobenzyl)amino]methyl}propyl 3-(2-chlorophenoxy)propanoate 850 (1R,2S)-2-amino-3-(4-fluorophenyl)-1-{[(3-methylbutyl)amino]methyl}propyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 852 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(4-chlorobenzoyl)-D-alaninate 854 (1R,2S)-2-amino-3-[3-(benzyloxy)-5-fluorophenyl]-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)sulfonyl]propanoate hydrochloride 856 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(4-methylphenyl)-4-oxobutanoate 858 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-oxo-4-{[3- (trifluoromethyl)phenyl]amino}butanoate 860 (1R,2S)-2-amino-3-(1,3-benzodioxol-5-yl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 862 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (5-pyridin-2-yl-2H-tetrazol-2-yl)acetate 864

866

(1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-(3-methyl-phenyl)propyl 3-[(dipropyl-amino)sulfonyl]propanoate 868 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl isoxazole-5-carboxylate 870 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (3,5-dimethoxyphenoxy)acetate 872 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(2,5-dimethyl-1H-pyrrol-1-yl)-3- hydroxybenzoate 874 (1R,2S)-2-amino-3-(3-bromophenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 5-(dipropylamino)-5-oxopentanoate 876 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-{[5-(cyclopentylmethyl)-1,3,4-thiadiazol-2- yl]amino}-4-oxobutanoate 878 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-[3-(trifluoromethyl)phenyl]propyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 880 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (3-oxo-1,2-benzisothiazol-2(3H)-yl)acetate 882 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-methyl-5-(pyrrolidin-1- ylcarbonyl)-1H-pyrrol-3-yl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]- 5-methylbenzoate 884 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(3,4-difluorophenyl)-4-oxobutanoate 886 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(2-naphthyl)-4-oxobutanoate 888 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4,6-diethoxypyridine-2-carboxylate 890 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(5-methyl-1H-pyrrol-2-yl)-4-oxobutanoate 892 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-({[2- (methylamino)ethyl]amino}sulfonyl)benzoate hydrochloride 894 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-methyl-5-(4-methylbenzoyl)benzoate 896 (1R,2S)-2-amino-3-(1,3-benzodioxol-5-yl)-1-[(benzylamino)methyl]propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 898 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(piperazin-1-ylsulfonyl)benzoate hydrochloride 900 (1R,2S)-2-amino-1-[({2-[4-(aminosulfonyl)phenyl]ethyl}amino)methyl]-3-(3,5- difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 902 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[2-hydroxy-1- (hydroxymethyl)ethyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 904 (1R,2S)-2-amino-3-(4-fluoro-3-methylphenyl)-1-{[(3- methylbutyl)amino]methyl}propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 906 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(3-oxo-2,1-benzisothiazol-1(3H)- yl)propanoate 908 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2,6-dihydroxypyrimidin-4-yl)acetate 910 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-[3- (trifluoromethyl)phenyl]propyl 5-(dipropylamino)-5-oxopentanoate 912 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(4-hydroxyphenyl)propyl 3- [(dipropylamino)sulfonyl]propanoate 914 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(3,4-difluorophenyl)-2-methyl-4- oxobutanoate 916 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-oxo-5-[(2-pyridin-2- ylethyl)amino]pentanoate 918 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl [2-(4-fluorophenyl)-1,3-benzoxazol-5- yl]acetate 920 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(anilinocarbonyl)glycinate 922 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(2,6-dimethoxybenzoyl)glycinate 924 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-(1,3-dithian-2-yl)-3-furoate 926 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-[2-oxo-2-(propylamino)ethyl]benzoate 928 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(3-bromophenyl)propyl 3- [(dipropylamino)sulfonyl]propanoate 930 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- iodobenzyl)amino]methyl}propyl 3-(2-fluorophenyl)propanoate 932 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-methylthiophene-2-carboxylate 934 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- iodobenzyl)amino]methyl}propyl [4-(benzyloxy)phenyl]acetate 936 (1R,2S)-2-arnino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl [(5,7-dimethyl[1,2,4]triazolo[4,3-a]pyrimidin- 3-yl)thio]acetate 938 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-[(1-acetyl-2,3-dihydro-1H-indol-7- yl)amino]-4-oxobutanoate 940 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-[(3-acetylphenyl)amino]-5-oxopentanoate 942 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(4-chlorophenoxy)-2-hydroxypropanoate 944 N³-[(1S,2R)-3-(benzylamino)-1-(3-fluoro-4-methoxybenzyl)-2-hydroxypropyl]- N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide 946 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(3-methylphenyl)propyl 3- (aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 948 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 1H-indole-7-carboxylate 950 (1R,2S)-2-amino-1-{[(3-methylbutyl)amino]methyl}-3-(3-methylphenyl)propyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 952 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(1,2,3-thiadiazol-4-yl)benzoate 954 (1R,2S)-2-amino-3-[3-(benzyloxy)-5-fluorophenyl]-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)sulfonyl]propanoate 956 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)- 2-{[(1-propylbutyl)sulfonyl]methyl}propanoate 958 (1R,2S)-2-amino-1-{[(3-methylbutyl)amino]methyl}-3-(4-methylphenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 960 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-[3-fluoro-5- (trifluoromethyl)phenyl]propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 962 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl [1-methyl-3-(methylthio)-1H-indol-2- yl]acetate 964 (1R,2S)-2-amino-3-(3,5-dichlorophenyl)-1-{[(3- methylbutyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 966 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl [(2-{[4-(1,3-oxazol-5-yl)phenyl]amino}-2- oxoethyl)thio]acetate 968

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-(2-furyl)-4-oxobutanoate 970

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(3-pyridin-2-yl-1,2,4-oxadiazol-5-yl)propanoate 972

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl [2-(acetylamino)-1,3-thiazol-4-yl]acetate 974 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl [(4-methyl-4H-1,2,4-triazol-3- yl)thio](phenyl)acetate 976 (1R,2S)-2-amino-3-(4-chlorophenyl)-1-{[(3-methylbutyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 978 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(1,3-benzothiazol-2-yl)butanoate 980 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-[(3-chloro-4-fluorophenyl)amino]-4- oxobutanoate 982 (1R,2S)-2-amino-3-[3-(benzyloxy)-5-fluorophenyl]-1-{[(3- methylbutyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 984 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl [(2-oxo-2,3-dihydroquinazolin-4- yl)thio]acetate 823 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(benzyloxy)-N- (3-ethylbenzyl)benzamide 825 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[(1S)-2-hydroxy- 1-methylethyl]-5-methyl-N′,N′-dipropylisophthalamide 827 N-[(2R,3S)-3-amino-2-hydroxy-4-(pentafluorophenyl)butyl]-5-methyl-N′,N′- dipropyl-N-[3-(trifluoromethyl)benzyl]isophthalamide 829 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4-(4-hydroxyphenyl)-4-oxobutanamide 831 N-{(2R,3S)-3-amino-2-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl}-3- [(dipropylamino)sulfonyl]-N-(3-methoxybenzyl)propanamide 833 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-(piperidin-3-ylsulfonyl)benzamide dihydrochloride 835 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-6-chloro-N-(3- ethylbenzyl)-4-hydroxyquinoline-2-carboxamide 837 N-[(2R,3S)-3-amino-2-hydroxy-4-(2-thienyl)butyl]-N-(3-methoxybenzyl)-N′,N′- dipropylpentanediamide 839 N-[(2R,3S)-3-amino-2-hydroxy-5-methylhexyl]-N-(3-methoxybenzyl)-5-methyl- N′,N′-dipropylisophthalamide 841 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-(6-oxo-3-phenylpyridazin-1(6H)-yl)acetamide 843 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-{4-[(methylsulfonyl)amino]phenyl}propanamide 845 N¹-[(2R,3S)-3-amino-4-(4-fluoro-3-methylphenyl)-2-hydroxybutyl]-N¹-(3- methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 847 N-[(2R,3S)-3-amino-2-hydroxy-4-(4-methylphenyl)butyl]-N-benzyl-5-methyl- N′,N′-dipropylisophthalamide 849 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(2- chlorophenoxy)-N-(3-iodobenzyl)propanamide 851 N¹-[(2R,3S)-3-amino-4-(4-fluorophenyl)-2-hydroxybutyl]-N¹-(3-methylbutyl)- N³,N³-dipropylbenzene-1,3,5-tricarboxamide 853

855

N-{(2R,3S)-3-amino-4-[3-(benzyloxy)-5-fluorophenyl]-2-hydroxybutyl}-3-[(dipropyl-amino)sulfonyl]-N-(3-methoxybenzyl)propanamidehydrochloride 857

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxy-butyl]-N-(3-ethylbenzyl)-4-(4-methylphenyl)-4-oxobutanamide 859

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-oxo-4-{[3-(trifluoromethyl)phenyl]amino}butanoate 861

N-[(2R,3S)-3-amino-4-(1,3-benzodioxol-5-yl)-2-hydroxy-butyl]-N-(3-methoxybenzyl)-5-methyl-N′,N′-dipropylisophthalamide 863

865

867 N-[(2R,3S)-3-amino-2-hydroxy-4-(3-methylphenyl)butyl]-3- [(dipropylamino)sulfonyl]-N-(3-methoxybenzyl)propanamide 869 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- ethylbenzyl)isoxazole-5-carboxamide 871 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-(3,5- dimethoxyphenoxy)-N-(3-ethylbenzyl)acetamide 873 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-(2,5-dimethyl- 1H-pyrrol-1-yl)-N-(3-ethylbenzyl)-3-hydroxybenzamide 875 N-[(2R,3S)-3-amino-4-(3-bromophenyl)-2-hydroxybutyl]-N-(3-methoxybenzyl)- N′,N′-dipropylpentanediamide 877 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-[5- (cyclopentylmethyl)-1,3,4-thiadiazol-2-yl]-N-(3-ethylbenzyl)succinamide 879 N¹-{(2R,3S)-3-amino-2-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl}-N¹-benzyl- N³,N³-dipropylbenzene-1,3,5-tricarboxamide 881 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-(3-oxo-1,2-benzisothiazol-2(3H)-yl)acetamide 883 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-[1- methyl-5-(pyrrolidin-1-ylcarbonyl)-1H-pyrrol-3-yl]-N′,N′- dipropylisophthalamide 885 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-(3,4- difluorophenyl)-N-(3-ethylbenzyl)-4-oxobutanamide 887 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4-(2-naphthyl)-4-oxobutanamide 889 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4,6-diethoxy-N-(3- ethylbenzyl)pyridine-2-carboxamide 891 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4-(5-methyl-1H-pyrrol-2-yl)-4-oxobutanamide 893 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-({[2-(methylamino)ethyl]amino}sulfonyl)benzamide hydrochloride 895 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- methoxybenzyl)-3-methyl-5-(4-methylbenzoyl)benzamide 897 N-[(2R,3S)-3-amino-4-(1,3-benzodioxol-5-yl)-2-hydroxybutyl]-N-benzyl-5- methyl-N′,N′-dipropylisophthalamide 899 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-(piperazin-1-ylsulfonyl)benzamide hydrochloride 901 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-{2-[4- (aminosulfonyl)phenyl]ethyl}-5-methyl-N′,N′-dipropylisophthalamide 903 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[2-hydroxy-1- (hydroxymethyl)ethyl]-5-methyl-N′,N′-dipropylisophthalamide 905 N¹-[(2R,3S)-3-amino-4-(4-fluoro-3-methylphenyl)-2-hydroxybutyl]-N¹-(3- methylbutyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 907 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-(3-oxo-2,1-benzisothiazol-1(3H)-yl)propanamide 909 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-(2,6- dihydroxyprimidin-4-yl)-N-(3-ethylbenzyl)acetamide 911 N-{(2R,3S)-3-amino-2-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl}-N-(3- methoxybenzyl)-N′,N′-dipropylpentanediamide 913 N-[(2R,3S)-3-amino-2-hydroxy-4-(4-hydroxyphenyl)butyl]-N-benzyl-3- [(dipropylamino)sulfonyl]propanamide 915 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-(3,4- difluorophenyl)-N-(3-ethylbenzyl)-2-methyl-4-oxobutanamide 917 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- N′-(2-pyridin-2-ylethyl)pentanediamide 919 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-[2-(4-fluorophenyl)-1,3-benzoxazol-5-yl]acetamide 921 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N²- (anilinocarbonyl)-N¹-(3-ethylbenzyl)glycinamide 923

925

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxy-butyl]-2-(1,3-dithian-2-yl)-N-(3-ethylbenzyl)-3-furamide 927

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxy-butyl]-N-(3-ethylbenzyl)-2-[2-oxo-2-(propylamino)ethyl]benzamide 929 N-[(2R,3S)-3-amino-4-(3-bromophenyl)-2-hydroxybutyl]-N-benzyl-3- [(dipropylamino)sulfonyl]propanamide 931 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(2-fluorophenyl)- N-(3-iodobenzyl)propanamide 933 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 5-methylthiophene-2-carboxamide 935 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-[4- (benzyloxy)phenyl]-N-(3-iodobenzyl)acetamide 937 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-[(5,7- dimethyl[1,2,4]triazolo[4,3-a]pyrimidin-3-yl)thio]-N-(3-ethylbenzyl)acetamide 939 N′-(1-acetyl-2,3-dihydro-1H-indol-7-yl)-N-[(2R,3S)-3-amino-4-(3,5- difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)succinamide 941 N′-(3-acetylphenyl)-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2- hydroxybutyl]-N-(3-ethylbenzyl)pentanediamide 943 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(4- chlorophenoxy)-N-(3-ethylbenzyl)-2-hydroxypropanamide 945 N³-[(1S,2R)-3-(benzylamino)-1-(3-fluoro-4-methoxybenzyl)-2-hydroxypropyl]- N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide 947 N¹-[(2R,3S)-3-amino-2-hydroxy-4-(3-methylphenyl)butyl]-N¹-benzyl-N³,N³- dipropylbenzene-1,3,5-tricarboxamide 949 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 1H-indole-7-carboxamide 951 N¹-[(2R,3S)-3-amino-2-hydroxy-4-(3-methylphenyl)butyl]-N¹-(3-methylbutyl)- N³,N³-diproplbenzene-1,3,5-tricarboxamide 953 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4-(1,2,3-thiadiazol-4-yl)benzamide 955 N-{(2R,3S)-3-amino-4-[3-(benzyloxy)-5-fluorophenyl]-2-hydroxybutyl}-3- [(dipropylamino)sulfonyl]-N-(3-methoxybenzyl)propanamide 957 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(4,4-dimethyl- 2,5-dioxoimidazolidin-1-yl)-N-(3-ethylbenzyl)-2-{[(1- propylbutyl)sulfonyl]methyl}propanamide 959 N-[(2R,3S)-3-amino-2-hydroxy-4-(4-methylphenyl)butyl]-5-methyl-N-(3- methylbutyl)-N′,N′-dipropylisophthalamide 961 N-{(2R,3S)-3-amino-4-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxybutyl}-N- benzyl-5-methyl-N′,N′-dipropylisophthalamide 963 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-[1-methyl-3-(methylthio)-1H-indol-2-yl]acetamide 965 N-[(2R,3S)-3-amino-4-(3,5-dichlorophenyl)-2-hydroxybutyl]-5-methyl-N-(3- methylbutyl)-N′,N′-dipropylisophthalamide 967 2-({2-[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]-2-oxoethyl}thio)-N-[4-(1,3-oxazol-5-yl)phenyl]acetamide 969 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4-(2-furyl)-4-oxobutanamide 971 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-(3-pyridin-2-yl-1,2,4-oxadiazol-5-yl)propanamide 973 2-[2-(acetylamino)-1,3-thiazol-4-yl]-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)- 2-hydroxybutyl]-N-(3-ethylbenzyl)acetamide 975 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]-2-phenylacetamide 977 N-[(2R,3S)-3-amino-4-(4-chlorophenyl)-2-hydroxybutyl]-5-methyl-N-(3- methylbutyl)-N′,N′-dipropylisophthalamide 979 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-(1,3- benzothiazol-2-yl)-N-(3-ethylbenzyl)butanamide 981 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-(3-chloro-4- fluorophenyl)-N-(3-ethylbenzyl)succinamide 983 N-{(2R,3S)-3-amino-4-[3-(benzyloxy)-5-fluorophenyl]-2-hydroxybutyl}-5- methyl-N-(3-methylbutyl)-N′,N′-dipropylisophthalamide 985 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-[(2-oxo-2,3-dihydroquinazolin-4-yl)thio]acetamide 986 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-methyl-5-(2-methylbenzoyl)benzoate 988 (1R,2S)-2-amino-3-(4-hydroxyphenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 5-(dipropylamino)-5-oxopentanoate 990 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(4-methylphenyl)propyl 3- (aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 992 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-propoxybenzoate 994 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}1-methyl-1H-indole-2-carboxylate 996 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4- yl)benzoate 998 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(3,4-difluorophenyl)-2-methoxy-4- oxobutanoate 1000 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl [3-(2-thienyl)-1H-pyrazol-1-yl]acetate 1002 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-anilino-5-oxopentanoate 1004 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2-thioxo-1,3-benzothiazol-3(2H)-yl)acetate 1006 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-cyclohexylpropyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 1008 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-(4- methoxyphenyl)propyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 1010 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (3-hydroxy-4-methylphenyl)acetate 1012 (1R,2S)-2-amino-3-[3-fluoro-5-(trifluoromethyl)phenyl]-1-{[(3- methylbutyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 1014 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 7-fluoro-4H-imidazo[5,1-c][1,4]benzoxazine- 3-carboxylate 1016 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)- 4-oxobutanoate 1018 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 1-benzofuran-3-carboxylate 1020 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(3,4-dichlorophenyl)amino]-3- oxopropanoate 1022 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-[3-fluoro-5- (trifluoromethyl)phenyl]propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 1024 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(1R)-2-hydroxy-1- methylethyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 1026 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(3-methylphenyl)propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 1028 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-oxo-5-(pyridin-3-ylamino)pentanoate 1030 (1R,2S)-2-amino-3-(3,5-difluorophenyly-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-methyl-4-oxo-4H-chromene-6-carboxylate 1032 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl ({2-[(5-methylisoxazol-3-yl)amino]-2- oxoethyl}thio)acetate 1034 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(1H-imidazol-1- yl)propyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 1036 (1R,2S)-2-amino-3-[3-fluoro-5-(trifluoromethyl)phenyl]-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-[dipropylamino)sulfonyl]propanoate 1038 (1R,2S)-2-amino-3-(4-hydroxyphenyl)-1-{[(3-methylbutyl)amino]methyl}propyl 3-[(dipropylamino)sulfonyl]propanoate 1040 (1R,2S)-2-amino-3-(1,3-benzodioxol-5-yl)-1-{[(3- methylbutyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 1042 (1R,2S)-2-amino-1-{[(3-methylbutyl)amino]methyl}-3-(2-thienyl)propyl 3- [(dipropylamino)sulfonyl]propanoate 1044 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-[(2,2-dimethylpropanoyl)amino]-2- hydroxybenzoate 1046 (1R,2S)-2-amino-3-(3-methoxyphenyl)-1-{[(3- methylbutyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 1048 (1R,2S)-2-amino-3-(4-fluorophenyl)-1-({[3- (trifluoromethyl)benzyl]amino}methyl)propyl 3-{[(3- methoxybenzyl)amino]sulfonyl}benzoate 1050 (1R,2S)-2-amino-1-{[(3-methylbutyl)amino]methyl}-3-[3- (trifluoromethyl)phenyl]propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 1052 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 6-(2-furoylamino)hexanoate 1054 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl [(1-phenyl-4,5-dihydro-1H-tetrazol-5- yl)thio]acetate 1056 (1S,2S)-2-amino-3-phenyl-1-({[3-(trifluoromethyl)benzyl]amino}methyl)propyl 3-{[(3-methoxybenzyl)amino]sulfonyl}benzoate 1058 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(3,4-dihydro-2H-chromen-6-yl)-4- oxobutanoate 1060 (1R,2S)-2-amino-3-(3-methoxyphenyl)-1-{[(3- methylbutyl)amino]methyl}propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 1062 (1R,2S)-2-amino-3-(3-fluoro-4-methylphenyl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 5-(dipropylamino)-5-oxopentanoate 1064 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl indolizine-2-carboxylate 1066 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-[3- (trifluoromethoxy)phenyl]propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate 1068 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl nicotinate 1-oxide 1070 (1R,2S)-2-amino-3-[3-(benzyloxy)-5-fluorophenyl)-1-{[(3- methylbutyl)amino]methyl}propyl 3-[(dipropylamino)sulfonyl]propanoate 1072 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- iodobenzyl)amino]methyl}propyl [(aminocarbonyl)oxy]acetate 1074 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2,3-dihydro-1H-cyclopenta[b]quinoline-9- carboxylate 1076 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-methyl-1H-pyrazole-5-carboxylate 1078 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-(benzoylamino)pentanoate 1080 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-[(methoxymethyl)thio]benzoate 1082 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(1,3-benzothiazol-2-yl)-3- methoxypropanoate 1084 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-{[(methylamino)carbonyl]amino}-3-(3- thienyl)propanoate 1086 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-pyridin-2-ylthiophene-2-carboxylate 1088 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-[3-(benzyloxy)-5- fluorophenyl]propyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 1090 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (5,6-dimethyl-2,4-dioxo-1,2,3,4- tetrahydropyridin-3-yl)acetate 1092 (1R,2S)-2-amino-3-(3-fluoro-4-methoxyphenyl)-1-{[(3- methylbutyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5- methylbenzoate 1094 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-isobutyl-1,3-dioxoisoindoline-5-carboxylate 1096 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-(acetylamino)-2-furoate 1098 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(4-methoxyphenyl)acetyl]glycinate 1100 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl isoquinoline-4-carboxylate 1102 (1R,2S)-2-amino-3-[3-(benzyloxy)phenyl]-1-{[(3- methylbutyl)amino]methyl}propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 1104 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (4-hydroxy-3-methoxyphenyl)acetate 1106 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl [(4-phenyl-4H-1,2,4-triazol-3-yl)thio]acetate 1108 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (3,5-dimethoxyphenyl)acetate 1110 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(3-methoxyphenyl)propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 1112 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2-ethyl-4H-[1,2,4]triazolo[1,5- a]benzimidazol-4-yl)acetate 1114 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(2-furyl)propyl 3- [(dipropylamino)carbonyl]-5-methylbenzoate 1116 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 7-chloro-1-benzofuran-2-carboxylate 1118 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2- yl)propanoate 1120 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(2-oxo-2H-1,3-benzoxazin-3(4H)- yl)propanoate 1122 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (pyrimidin-2-ylthio)acetate 1124 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-{[3-(aminocarbonyl)-4,5,6,7-tetrahydro-1- benzothien-2-yl]amino}-4-oxobutanoate 1126 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl [(5-phenyl-1,3,4-oxadiazol-2-yl)thio]acetate 1128 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl quinoline-6-carboxylate 1130 (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(2-furyl)propyl 3-(aminocarbonyl)- 5-[(dipropylamino)carbonyl]benzoate 1132 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-4- oxobutanoate 1134 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(1H-indol-3-yl)-1H-pyrazole-5-carboxylate 1136 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-hydroxy-4- {[(methylamino)carbonothioyl]amino}benzoate 1138 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 6-chloronicotinate 1140 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(3-hydroxyphenyl)-4-oxobutanoate 1142 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (phthalazin-1-ylthio)acetate 1144 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl [(1-oxidopyridin-2-yl)thio]acetate 1146 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(acetylamino)-5-fluoro-1H-indole-2- carboxylate 1148 (1S,2S)-2-amino-3-phenyl-1-({[3-(trifluoromethyl)benzyl]amino}methyl)propyl 3-{[(3-chlorobenzyl)amino]sulfonyl}benzoate 1150 (1R,2S)-2-amino-3-[4-(benzyloxy)phenyl]-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-(aminocarbonyl)-5- [(dipropylamino)carbonyl]benzoate 1152 (1R,2S)-2-amino-3-(1,3-benzodioxol-5-yl)-1-[(benzylamino)methyl]propyl 3-{[(3- (aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate 1154 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-(3,4-dichlorophenyl)-2-hydroxy-3-methyl- 4-oxobutanoate 1156 (1R,2S)-2-amino-1-{[(3-methylbutyl)amino)methyl}-3-[3- (trifluoromethoxy)phenyl]propyl 3-[(dipropylamino)sulfonyl]propanoate 1158 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino)methyl}propyl 4-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]-4- oxobutanoate 1160 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2-ethyl-1H-benzimidazol-1-yl)acetate 1162 (1R,2S)-2-amino-3-(1,3-benzodioxol-5-yl)-1-{[(3- methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)sulfonyl]propanoate 1164 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(2-oxo-1,3-benzoxazol-3 (2H)-yl)propanoate 1166 (1R,2S)-2-amino-3-(3,5-dichlorophenyl)-1-{[(3- methylbutyl)amino]methyl}propyl 3-[(dipropylamino)sulfonyl]propanoate 1168 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-[(6-methylpyridin-2-yl)amino]-4- oxobutanoate 1170 4-((1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl) 3-ethyl (4R)-1,3-oxazolidine-3,4- dicarboxylate 987 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- methoxybenzyl)-3-methyl-5-(2-methylbenzoyl)benzamide 989

N-[(2R,3S)-3-amino-2-hydroxy-4-(4-hydroxyphenyl)butyl]-N-(3-methoxy-benzyl)-N′,N′-dipropylpentanediamide 991

N¹-[(2R,3S)-3-amino-2-hydroxy-4-(4-methylphenyl)butyl]-N¹-benzyl-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 993

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-4-propoxy-benzamide 995

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-1-methyl-1H-indole-2-carboxamide 997

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-chloro-N-(3-ethylbenzyl)-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzamide 999

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-(3,4-difluorophenyl)-N-(3-ethylbenzyl)-2-methoxy-4-oxobutanamide 1001

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-[3-(2-thienyl)-1H-pyrazol-1-yl]acetamide 1003 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- N′-phenylpentanediamide 1005 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-(2-thioxo-1,3-benzothiazol-3(2H)-yl)acetamide 1007 N-[(2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutyl]-N-benzyl-5-methyl-N′,N′- dipropylisophthalamide 1009 N¹-[(2R,3S)-3-amino-2-hydroxy-4-(4-methoxyphenyl)butyl]-N¹-(3- methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 1011 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-(3-hydroxy-4-methylphenyl)acetamide 1013 N-{(2R,3S)-3-amino-4-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxybutyl}-5- methyl-N-(3-methylbutyl)-N′,N′-dipropylisophthalamide 1015 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 7-fluoro-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide 1017 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-(3,4-dihydro-2H- 1,5-benzodioxepin-7-yl)-N-(3-ethylbenzyl)-4-oxobutanamide 1019 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 1-benzofuran-3-carboxamide 1021 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-(3,4- dichlorophenyl)-N-(3-ethylbenzyl)malonamide 1023 N¹-{(2R,3S)-3-amino-4-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxybutyl}- N¹-benzyl-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 1025 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[(1R)-2-hydroxy- 1-methylethyl]-5-methyl-N′,N′-dipropylisophthalamide 1027 N-[(2R,3S)-3-amino-2-hydroxy-4-(3-methylphenyl)butyl]-N-benzyl-5-methyl- N′,N′-dipropylisophthalamide 1029 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- N′-pyridin-3-ylpentanediamide 1031 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-methyl-4-oxo-4H-chromene-6-carboxylate 1033 2-({2-[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]-2-oxoethyl}thio)-N-(5-methylisoxazol-3-yl)acetamide 1035 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[3-(1H-imidazol- 1-yl)propyl]-5-methyl-N′,N′-dipropylisophthalamide 1037 N-{(2R,3S)-3-amino-4-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxybutyl}-3- [(dipropylamino)sulfonyl]-N-(3-methoxybenzyl)propanamide 1039 N-[(2R,3S)-3-amino-2-hydroxy-4-(4-hydroxyphenyl)butyl]-3- [(dipropylamino)sulfonyl]-N-(3-methylbutyl)propanamide 1041 N-[(2R,3S)-3-amino-4-(1,3-benzodioxol-5-yl)-2-hydroxybutyl]-5-methyl-N-(3- methylbutyl)-N′,N′-dipropylisophthalamide 1043 N-[(2R,3S)-3-amino-2-hydroxy-4-(2-thienyl)butyl]-3-[(dipropylamino)sulfonyl]- N-(3-methylbutyl)propanamide 1045 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-[(2,2- dimethylpropanoyl)amino]-N-(3-ethylbenzyl)-2-hydroxybenzamide 1047 N-[(2R,3S)-3-amino-2-hydroxy-4-(3-methoxyphenyl)butyl]-5-methyl-N-(3- methylbutyl)-N′,N′-dipropylisophthalamide 1049 N-[(2R,3S)-3-amino-4-(4-fluorophenyl)-2-hydroxybutyl]-3-{[(3- methoxybenzyl)amino]sulfonyl}-N-[3-(trifluoromethyl)benzyl]benzamide 1051 N-{(2R,3S)-3-amino-2-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl}-5-methyl- N-(3-methylbutyl)-N′,N′-dipropylisophthalamide 1053 N-{6-[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]-6-oxohexyl}-2-furamide 1055 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-[(1-phenyl-4,5-dihydro-1H-tetrazol-5-yl)thio]acetamide 1057 N-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3-{[(3- methoxybenzyl)amino]sulfonyl}-N-[3-trifluoromethyl)benzyl]benzamide 1059 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-(3,4-dihydro-2H- chromen-6-yl)-N-(3-ethylbenzyl)-4-oxobutanamide 1061 N¹-[(2R,3S)-3-amino-2-hydroxy-4-(3-methoxyphenyl)butyl]-N¹-(3-methylbutyl)- N³,N³-dipropylbenzene-1,3,5-tricarboxamide 1063 N-[(2R,3S)-3-amino-4-(3-fluoro-4-methylphenyl)-2-hydroxybutyl]-N-(3- methoxybenzyl)-N′,N′-dipropylpentanediamide 1065 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- ethylbenzyl)indolizine-2-carboxamide 1067 N-{(2R,3S)-3-amino-2-hydroxy-4-[3-(trifluoromethoxy)phenyl]butyl}-N-benzyl- 5-methyl-N′,N′-dipropylisophthalamide 1069 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- ethylbenzyl)nicotinamide 1-oxide 1071 N-{(2R,3S)-3-amino-4-[3-(benzyloxy)-5-fluorophenyl]-2-hydroxybutyl}-3- [(dipropylamino)sulfonyl]-N-(3-methylbutyl)propanamide 1073 2-[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- iodobenzyl)amino]-2-oxoethyl carbamate 1075 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2,3-dihydro-1H-cyclopenta[b]quinoline-9-carboxamide 1077 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-methyl-1H-pyrazole-5-carboxamide 1079 N-{5-[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]-5-oxopentyl}benzamide 1081 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 4-[(methoxymethyl)thio]benzamide 1083 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(1,3- benzothiazol-2-yl)-N-(3-ethylbenzyl)-3-methoxypropanamide 1085 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-{[methylamino)carbonyl]amino}-3-(3-thienyl)propanamide 1087 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 5-pyridin-2-ylthiophene-2-carboxamide 1089 N¹-{(2R,3S)-3-amino-4-[3-(benzyloxy)-5-fluorophenyl]-2-hydroxybutyl}-N¹- benzyl-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 1091 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-(5,6-dimethyl- 2,4-dioxo-1,2,3,4-tetrahydropyridin-3-yl)-N-(3-ethylbenzyl)acetamide 1093 N-[(2R,3S)-3-amino-4-(3-fluoro-4-methoxyphenyl)-2-hydroxybutyl]-5-methyl- N-(3-methylbutyl)-N′,N′-dipropylisophthalamide 1095 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-isobutyl-1,3-dioxoisoindoline-5-carboxamide 1097 5-(acetylamino)-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N- (3-ethylbenzyl)-2-furamide 1099 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3- ethylbenzyl)-N²-[(4-methoxyphenyl)acetyl]glycinamide 1101 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- ethylbenzyl)isoquinoline-4-carboxamide 1103 N¹-{(2R,3S)-3-amino-4-[3-(benzyloxy)phenyl]-2-hydroxybutyl}-N¹-(3- methylbutyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 1105 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-(4-hydroxy-3-methoxyphenyl)acetamide 1107 N-[(2R,3-S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl) 2-[(4-phenyl-4H-1,2,4-triazol-3-yl)thio]acetamide 1109 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-(3,5- dimethoxyphenyl)-N-(3-ethylbenzyl)acetamide 1111 N-[(2R,3S)-3-amino-2-hydroxy-4-(3-methoxyphenyl)butyl]-N-benzyl-5-methyl- N′,N′-dipropylisophthalamide 1113 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-(2-ethyl-4H-[1,2,4]triazolo[1,5-a]benzimidazol-4-yl)acetamide 1115 N-[(2R,3S)-3-amino-4-(2-furyl)-2-hydroxybutyl]-N-benzyl-5-methyl-N′,N′- dipropylisophthalamide 1117 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-7-chloro-N-(3- ethylbenzyl)-1-benzofuran-2-carboxamide 1119 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-(1,3-dioxo-1,3- dihydro-2H-isoindol-2-yl)-N-(3-ethylbenzyl)propanamide 1121 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-(2-oxo-2H-1,3-benzoxazin-3(4H)-yl)propanamide 1123 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-(pyrimidin-2-ylthio)acetamide 1125 N¹-[3-(aminocarbonyl)-4,5,6,7-tetrahydro-1-benzothien-2-yl]-N-[(2R,3S)-3- amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)succinamide 1127 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-[(5-phenyl-1,3,4-oxadiazol-2-yl)thio]acetamide 1129 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- ethylbenzyl)quinoline-6-carboxamide 1131

N-[(2R,3S)-3-amino-4-(2-furyl)-2-hydroxybutyl]-N¹-benzyl-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 1133

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxy-butyl]-4-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-(3-ethylbenzyl)-4-oxobutanamide 1135

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxy-butyl]-N-(3-ethylbenzyl)-3-(1H-indol-3-yl)-1H-pyrazole-5-carboxamide 1137

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxy-butyl]-N-(3-ethylbenzyl)-2-hydroxy-4-{[(methylamino)carbonothioyl]amino}benzamide 1139

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxy-butyl]-6-chloro-N-(3-ethyl-benzyl)nicotinamide 1141

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxy-butyl]-N-(3-ethylbenzyl)-4-(3-hydroxyphenyl)-4-oxobutanamide 1143

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxy-butyl]-N-(3-ethylbenzyl)-2-(phthalazin-1-ylthio)acetamide 1145

N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxy-butyl]-N-(3-ethylbenzyl)-2-[(1-oxidopyridin-2-yl)thio]acetamide 1147

3-(acetylamino)-N-[(2R,3S)-3-amino-4-(3,5-difluoro-phenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-5-fluoro-1H-indole-2-carboxamide 1149 N-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3-{[(3- chlorobenzyl)amino]sulfonyl}-N-[3-(trifluoromethyl)benzyl]benzamide 1151 N¹-{(2R,3S)-3-amino-4-[4-(benzyloxy)phenyl]-2-hydroxybutyl}-N¹-(3- methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide 1153 N¹-[(2R,3S)-3-amino-4-(1,3-benzodioxol-5-yl)-2-hydroxybutyl]-N¹-benzyl- N³,N³-dipropylbenzene-1,3,5-tricarboxamide 1155 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-(3,4- dichlorophenyl)-N-(3-ethylbenzyl)-2-hydroxy-3-methyl-4-oxobutanamide 1157 N-{(2R,3S)-3-amino-2-hydroxy-4-[3-(trifluoromethoxy)phenyl]butyl}-3- [(dipropylamino)sulfonyl]-N-(3-methylbutyl)propanamide 1159 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- N′-(5-methyl-1,3,4-thiadiazol-2-yl)succinamide 1161 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-(2-ethyl-1H- benzimidazol-1-yl)-N-(3-ethylbenzyl)acetamide 1163 N-[(2R,3S)-3-amino-4-(1,3-benzodioxol-5-yl)-2-hydroxybutyl]-3- [(dipropylamino)sulfonyl]-N-(3-methoxybenzyl)propanamide 1165 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 3-(2-oxo-1,3-benzoxazol-3(2H)-yl)propanamide 1167 N-[(2R,3S)-3-amino-4-(3,5-dichlorophenyl)-2-hydroxybutyl]-3- [(dipropylamino)sulfonyl]-N-(3-methylbutyl)propanamide 1169 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- N′-(6-methylpyridin-2-yl)succinamide 1171 ethyl (4R)-4-{[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]carbonyl}-1,3-oxazolidine-3-carboxylate 1172 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfinyl)-N-(methoxycarbonyl)-D- alaninate 1174 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl S-butyl-N-(methoxycarbonyl)-D-cysteinate 1176 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(benzyloxy)carbonyl]-3-[(4,4,4- trifluorobutyl)sulfonyl]-D-alaninate 1178 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(benzyloxy)carbonyl]-3-[(4,4,4- trifluorobutyl)sulfinyl]-D-alaninate 1180 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(benzyloxy)carbonyl]-S-(4,4,4- trifluorobutyl)-D-cysteinate 1182 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-(methoxycarbonyl)-D- alaninate 1184 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-[(2,2,2- trifluoroethoxy)carbonyl]-D-alaninate 1186 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-[(2- cyanoethoxy)carbonyl]-D-alaninate 1188 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-{[(3R)-pyrrolidin-3- yloxy]carbonyl}-D-alaninate 1190 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-{[(3S)-tetrahydrofuran-3- yloxy]carbonyl}-D-alaninate 1192 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-{[2-(acetylamino)ethoxy]carbonyl}-3- (butylsulfonyl)-D-alaninate 1194 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-[(pyridin-3- ylmethoxy)carbonyl]-D-alaninate 1196 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-[(pyridin-4- ylmethoxy)carbonyl]-D-alaninate 1198 (1R,2S)-2-amino-1-[(cyclopropylamino)methyl]-3-(3,5-difluorophenyl)propyl 3- (butylsulfonyl)-N-(methoxycarbonyl)-D-alaninate 1200 (1R,2S)-2-amino-1-[(cyclopropylamino)methyl]-3-(3,5-difluorophenyl)propyl 3- (butylsulfonyl)-N-[(2-cyanoethoxy)carbonyl]-D-alaninate 1202 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- methylbutyl)amino]methyl}propyl N-[(benzyloxy)carbonyl]-3-(butylsulfonyl)- D-alaninate 1204 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- methylbutyl)amino]methyl}propyl 3-(butylsulfonyl)-N-(methoxycarbonyl)-D- alaninate 1206 (1R,2S)-2-amino-1-[(cyclopropylamino)methyl]-3-(3,5-difluorophenyl)propyl N- [(2-cyanoethoxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D-alaninate 1208 (1R,2S)-2-amino-1-[(cyclopropylamino)methyl]-3-(3,5-difluorophenyl)propyl N- {[2-(acetylamino)ethoxy]carbonyl}-3-[(1-propylbutyl)sulfonyl]-D-alaninate 1210 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- methylbutyl)amino]methyl}propyl N-(methoxycarbonyl)-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1212 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- methylbutyl)amino]methyl}propyl N-[(benzyloxy)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1214 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-{[2-(diethylamino)-2-oxoethoxy]carbonyl}- 3-[(1-propylbutyl)sulfonyl]-D-alaninate 1216 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(methoxycarbonyl)-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1218 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(isopropoxycarbonyl)-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1220 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(cyclopropylmethoxy)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1222 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(allyloxy)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1224 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(2-cyanoethoxy)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1226 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-{[2-(acetylamino)ethoxy]carbonyl}-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1228 (1R,2S)-2-amino-3-(3,5-difluorophenyly-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-[(pyridin-3- ylmethoxy)carbonyl]-D-alaninate 1230 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-[(pyridin-4- ylmethoxy)carbonyl]-D-alaninate 1232 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2R)-2-{[(benzyloxy)carbonyl]amino}-4- (methylsulfonyl)butanoate 1234 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(benzyloxy)carbonyl]-3-(butylsulfonyl)-D- alaninate 1236 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(benzyloxy)carbonyl]-3-(butylsulfonyl)-L- alaninate 1238 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(1R)-2-hydroxy-1- phenylethyl]amino}methyl)propyl N-[(benzyloxy)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1240 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(1R)-2-methoxy-1- phenylethyl]amino}methyl)propyl N-[(benzyloxy)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1242 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(1S)-2-methoxy-1- phenylethyl]amino}methyl)propyl N-[(benzyloxy)carbonyl]-3-[(1- propylbutyl)su1fonyl]-D-alaninate 1244 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethylphenyl)cyclopropyl]amino}methyl)propyl N-[(benzyloxy)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1246 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-[(prop-2-yn-1- yloxy)carbonyl]-D-alaninate 1248 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(2-methoxyethoxy)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1250 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-({[(3R)-1-acetylpyrrolidin-3- yl]oxy}carbonyl)-3-[(1-propylbutyl)sulfonyl]-D-alaninate 1252 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-{[(3S)- tetrahydrofuran-3-yloxy]carbonyl}-D-alaninate 1254 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-{[(3S)- tetrahydrofuran-3-yloxy]carbonyl}-L-alaninate 1256 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(benzyloxy)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1258 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(benzyloxy)carbonyl]-3-[(1- propylbutyl)sulfonyl]-L-alaninate 1260 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethylphenyl)cyclopropyl]amino}methyl)propyl N-[(benzyloxy)carbonyl]-3-[(1- propylbutyl)sulfonyl]alaninate 1262 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(benzyloxy)carbonyl]-3-[(1- propylbutyl)sulfonyl]alaninate 1264 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- methylbutyl)amino]methyl}propyl N-[(benzyloxy)carbonyl]-3-[(1- propylbutyl)sulfonyl]alaninate 1266 (1R,2S)-2-amino-1-[(cyclopropylamino)methyl]-3-(3,5-difluorophenyl)propyl N- [(benzyloxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]alaninate 1268 (1R,2S)-2-amino-1-{[(cyclopropylmethyl)amino]methyl}-3-(3,5- difluorophenyl)propyl N-[(benzyloxy)carbonyl]-3-[(1- propylbutyl)sulfonyl]alaninate 1270 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylphenyl)amino]methyl}propyl N-[(benzyloxy)carbonyl]-3-[(1- propylbutyl)sulfonyl]alaninate 1272 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-[({2-[3- (trifluoromethyl)phenyl]ethyl}amino)methyl]propyl N-[(benzyloxy)carbonyl]-3- [(1-propylbutyl)sulfonyl]alaninate 1274 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-[(pyridin-3- ylmethoxy)carbonyl]alaninate 1276 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-{[(3S)- tetrahydrofuran-3-yloxy]carbonyl}alaninate 1278 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-{[(3R)- tetrahydrofuran-3-yloxy]carbonyl}alaninate 1280 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 3-[(1- propylbutyl)sulfonyl]-N-{[(3S)-tetrahydrofuran-3-yloxy]carbonyl}alaninate 1282 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-({[(3R)-1-acetylpyrrolidin-3- yl]oxy}carbonyl)-3-[(1-propylbutyl)sulfonyl]alaninate 1284 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-{[(3R)- pyrrolidin-3-yloxy]carbonyl}alaninate 1286 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-({[(3R)-1-benzylpyrrolidin-3- yl]oxy}carbonyl)-3-[(1-propylbutyl)sulfonyl]alaninate 1288 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-({[(3R)-1,1-dioxidotetrahydro-3- thienyl]oxy}carbonyl)-3-[(1-propylbutyl)sulfonyl]alaninate 1290 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-{[(3R)- tetrahydro-3-thienyloxy]carbonyl}alaninate 1292 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(cyclopentyloxy)carbonyl]-3-[(1- propylbutyl)sulfonyl]alaninate 1294 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(cyclohexyloxy)carbonyl]-3-[(1- propylbutyl)sulfonyl]alaninate 1296 (1R,2S)-2-amino-1-[(cyclopropylamino)methyl]-3-(3,5-difluorophenyl)propyl 3- [(1-propylbutyl)sulfonyl]-N-[(tetrahydro-2H-pyran-4-yloxy)carbonyl]alaninate 1298

1300

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-({[1-(methyl-sulfonyl)piperidin-4-yl]oxy}carbonyl)-3-[(1-propylbutyl)sulfonyl]alaninate 1302

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-{[(1-acetyl-piperidin-4-yl)oxy]carbonyl}-3-[(1-propylbutyl)sulfonyl]alaninate 1304

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-({[(2R)-5-oxo-pyrrolidin-2-yl]methoxy}carbonyl)-3-[(1-propylbutyl)sulfonyl]alaninate 1306

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-({[(2S)-5-oxo-pyrrolidin-2-yl]methoxy}carbonyl)-3-[(1-propylbutyl)sulfonyl]alaninate 1308

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-[(2-methoxyethoxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]alaninate 1310

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-[(benzyloxy)carbonyl]-3-(butylsulfonyl)alaninate 1312 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl N- [(benzyloxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]alaninate 1314 N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2- hydroxy-4-(phenylsulfonyl)butanamide hydrochloride 1316 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N²-[(benzyloxy)carbonyl]-N⁵,N⁵-dipropyl-L- glutaminate 1318 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N²-[(benzyloxy)carbonyl]-N⁵,N⁵-dipropyl-D- glutaminate 1320 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-(3,3,3- trifluoropropanoyl)-D-alaninate 1322 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-(trifluoroacetyl)-D- alaninate 1324 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-acetyl-3-(butylsulfonyl)-D-alaninate 1326 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-isonicotinoyl-D-alaninate 1328 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino)methyl}propyl 3-(butylsulfonyl)-N-(cyclopropylcarbonyl)-D- alaninate 1330 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl β-alanyl-3-(butylsulfonyl)-D-alaninate 1332 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl glycyl-3-(butylsulfonyl)-D-alaninate 1334 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N,N-dimethylglycyl-3-(butylsulfonyl)-D- alaninate 1336 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N,N-dimethyl-β-alanyl-3-(butylsulfonyl)-D- alaninate 1338 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-(methoxyacetyl)-D- alaninate 1340 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-(pyridin-3-ylcarbonyl)-D- alaninate 1342 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-[(2,4-dimethyl-1,3- thiazol-5-yl)carbonyl]-D-alaninate 1344 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-{[3-(trifluoromethyl)-1H- pyrazol-4-yl]carbonyl}-D-alaninate 1346 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-[(3-methyl-1H-pyrazol-5- yl)carbonyl]-D-alaninate 1348 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-(1H-imidazol-4- ylcarbonyl)-D-alaninate 1350 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2R)-5-hydroxy-2- [(methoxycarbonyl)amino]nonanoate 1352 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-[(6-hydroxypyridin-3- yl)carbonyl]-D-alaninate 1354 (1R,2S)-2-amino-1-[(cyclopropylamino)methyl]-3-(3,5-difluorophenyl)propyl 3- (butylsulfonyl)-N-(pyridin-3-ylcarbonyl)-D-alaninate 1356 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- methylbutyl)amino]methyl}propyl N-acetyl-3-(butylsulfonyl)-D-alaninate 1358 (1R,2S)-2-amino-1-[(cyclopropylamino)methyl]-3-(3,5-difluorophenyl)propyl N- (cyclopropylcarbonyl)-3-[(1-propylbutyl)sulfonyl]-D-alaninate 1360 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- methylbutyl)amino]methyl}propyl N-acetyl-3-[(1-propylbutyl)sulfonyl]-D- alaninate 1362 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-isonicotinoyl-3-[(1-propylbutyl)sulfonyl]- D-alaninate 1364 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(5-bromopyridin-3-yl)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1366 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(5-chloropyridin-3-yl)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1368 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(3-fluorobenzoyl)-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1370 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(5-methylpyridin-3-yl)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1372 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-phenylglycyl-3-[(1-propylbutyl)sulfonyl]- D-alaninate 1374 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-{[3- (trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}-D-alaninate 1376 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(3-methyl-1H-pyrazol-5-yl)carbonyl]-3- [(1-propylbutyl)sulfonyl]-D-alaninate 1378 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-(1,3-thiazol-4- ylcarbonyl-D-alaninate 1380 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(1-acetylpiperidin-4-yl)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1382 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[4-(acetylamino)butanoyl]-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1384 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-acetyl-β-alanyl-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1386 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(chloroacetyl)-3-[(1-propylbutyl)sulfonyl]- D-alaninate 1388 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(methoxyacetyl)-3-[(1- propylbutyl)sulfonyl)-D-alaninate 1390 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(3-methoxypropanoyl)-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1392 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(2,2-dimethylpropanoyl)-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1394 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-isobutyryl-3-[(1-propylbutyl)sulfonyl]-D- alaninate 1396 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-butyryl-3-[(1-propylbutyl)sulfonyl]-D- alaninate 1398 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-acetyl-3-[(1-propylbutyl)sulfonyl]-D- alaninate 1400 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethylphenyl)cyclopropyl]amino}methyl)propyl 3-[(1-propylbutyl)sulfonyl]-N- (pyridin-3-ylcarbonyl)-D-alaninate 1402 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethylphenyl)cyclopropyl]amino}methyl)propyl N-isonicotinoyl-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1404 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethylphenyl)cyclopropyl]amino}methyl)propyl N-(3-hydroxybenzoyl)-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1406 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-(pyridin-3- ylcarbonyl)-D-alaninate 1408 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(3-hydroxybenzoyl)-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1410 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-([(3- ethylbenzyl)amino]methyl}propyl N-(cyclopropylcarbonyl)-3-[(1- propylbutyl)sulfonyl]-D-alaninate 1412 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-propionyl-3-[(1-propylbutyl)sulfonyl]-D- alaninate 1414 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-([(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-(pyridin-3- ylcarbonyl)alaninate 1416 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethylphenyl)cyclopropyl]amino}methyl)propyl N-(3-hydroxybenzoyl)-3-[(1- propylbutyl)sulfonyl]alaninate 1418 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethylphenyl)cyclopropyl]amino}methyl)propyl N-isonicotinoyl-3-[(1- propylbutyl)sulfonyl]alaninate 1420 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(6-oxo-1,4,5,6-tetrahydropyridazin-3- yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]alaninate 1422 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-oxo-D-prolyl-3-[(1- propylbutyl)sulfonyl]alaninate hydrochloride 1424 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 5-oxo-L-prolyl-3-[(1- propylbutyl)sulfonyl]alaninate 1426 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[3-(4-oxo-2-thioxo-1,3-thiazolidin-3- yl)propanoyl]-3-[(1-propylbutyl)sulfonyl]alaninate 1428 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(piperidin-4-ylcarbonyl)-3-[(1- propylbutyl)sulfonyl]alaninate 1430 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(2,4-dimethyl-1,3-thiazol-5-yl)carbonyl]- 3-[(1-propylbutyl)sulfonyl]alaninate 1432 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-{[2-methyl-4-(trifluoromethyl)-1,3-thiazol- 5-yl]carbonyl}-3-[(1-propylbutyl)sulfonyl]alaninate 1434 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(3,5-dimethylisoxazol-4-yl)carbonyl]-3- [(1-propylbutyl)sulfonyl]alaninate 1436 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(3-methyl-1H-pyrazol-5-yl)carbonyl]-3- [(1-propylbutyl)sulfonyl]alaninate 1438 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-(1H-pyrazol-4- ylcarbonyl)alaninate 1440 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(1H-imidazol-5-ylcarbonyl)-3-[(1- propylbutyl)sulfonyl]alaninate 1442 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(1H-imidazol-4-ylacetyl)-3-[(1- propylbutyl)sulfonyl]alaninate 1444 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-(pyrazin-2- ylcarbonyl)alaninate 1446 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(2,6-dihydroxyisonicotinoyl)-3-[(1- propylbutyl)sulfonyl]alaninate 1448 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(6-hydroxypyridin-3-yl)carbonyl]-3-[(1- propylbutyl)sulfonyl]alaninate 1450 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-[(6-chloropyridin-3-yl)carbonyl]-3-[(1- propylbutyl)sulfonyl]alaninate 1452 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-isonicotinoyl-3-[(1- propylbutyl)sulfonyl]alaninate 1454 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-(pyridin-3- ylcarbonyl)alaninate 1456 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-([(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-(pyridin-2- ylcarbonyl)alaninate 1458 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(1H-indol-6-ylcarbonyl)-3-[(1- propylbutyl)sulfonyl]alaninate hydrochloride 1460 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-(3,4,5- trimethoxybenzoyl)alaninate 1462 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(2-methylbenzoyl)-3-[(1- propylbutyl)sulfonyl]alaninate 1464 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(3-hydroxybenzoyl)-3-[(1- propylbutyl)sulfonyl]alaninate 1466 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(3-methylbenzoyl)-3-[(1- propylbutyl)sulfonyl]alaninate 1468 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(3-ethylbenzoyl)-3-[(1- propylbutyl)sulfonyl]alaninate 1470 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(3-chlorobenzoyl)-3-[(1- propylbutyl)sulfonyl]alaninate 1472 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-[4- (trifluoromethyl)benzoyl]alaninate 1474 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(4-methoxybenzoyl)-3-[(1- propylbutyl)sulfonyl]alaninate 1476 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-[4- (trifluoromethyl)benzoyl]alaninate 1478

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-(cyclohexyl-carbonyl)-3-[(1-propylbutyl)sulfonyl]alaninate 1480

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-benzoyl-3-[(1-propylbutyl)sulfonyl]alaninate 1482

(1R,2S)-2-amino-1-[(cyclopropylamino)methyl]-3-(3,5-difluorophenyl)propylN-benzoyl-3-[(1-propyl-butyl)sulfonyl]alaninate 1484

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-(phenylacetyl)-3-[(1-propylbutyl)sulfonyl]alaninate 1486

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-(3-phenylpro-panoyl)-3-[(1-propylbutyl)sulfonyl]alaninate 1488

(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(benzoylamino)-2-{[(1-propylbutyl)sulfonyl]methyl}propanoate 1490

(1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl N-(cyclopropylacetyl)-3-[(1-propylbutyl)sulfonyl]alaninate 1492

(1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl N-[(methylsulfonyl)acetyl]-3-[(1-propylbutyl)sulfonyl]alaninate 1494

(1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl N-[(methylthio)acetyl]-3-[(1-propylbutyl)sulfonyl]alaninate 1496

1498

(1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl N-[4-(methylamino)-4-oxo-butanoyl]-3-[(1-propyl-butyl)sulfonyl]alaninate 1500

1502 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl N- (methylsulfonyl)glycyl-3-[(1-propylbutyl)sulfonyl]alaninate 1504 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl N- acetyl-3-(phenylsulfonyl)alaninate 1506 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2S)-2- [(4-methoxy-4-oxobutanoyl)amino]-5-oxo-5-piperidin-1-ylpentanoate 1508 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2R)-2- {[(benzyloxy)carbonyl]amino}-5-oxo-5-piperidin-1-ylpentanoate 1510 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2R)-2- [(3-ethoxy-3-oxopropanoyl)amino]-5-oxo-5-piperidin-1-ylpentanoate 1512 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl N²-(4- methoxy-4-oxobutanoyl)-N⁵,N⁵-dipropyl-D-glutaminate 1514 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2R)-2- [(4-methoxy-4-oxobutanoyl)amino]-5-oxo-5-piperidin-1-ylpentanoate 1516 (1R,28)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2R)-2- [(5-methoxy-5-oxopentanoyl)amino]-5-oxo-5-piperidin-1-ylpentanoate 1518 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-(acetyloxy)-3-(butylsulfonyl)propanoate 1520 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl S-butyl-D-cysteinate 1522 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfinyl)-D-alaninate 1524 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-D-alaninate 1526 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-L-alaninate 1528 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- methylbutyl)amino]methyl}propyl 3-(butylsulfonyl)-D-alaninate 1530 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethylphenyl)cyclopropyl]amino}methyl)propyl 3-[(1-propylbutyl)sulfonyl]-D- alaninate 1532 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-L-alaninate 1534 (1R,2S)-2 -amino-1-[(cyclopropylamino)methyl]-3-(3,5-difluorophenyl)propyl 3- [(1-propylbutyl)sulfonyl]-D-alaninate 1536 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- methylbutyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-D-alaninate 1538 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-D-alaninate 1540 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]alaninate 1542 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(phenoxyacetyl)-3-[(1- propylbutyl)sulfonyl]alaninate 1544 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-{[(5-chloro-2-thienyl)thio]peroxy}-3-[(1- propylbutyl)sulfonyl]alaninate 1546 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl N-(phenylsulfonyl)-3-[(1- propylbutyl)sulfonyl]alaninate 1548 (1R,2S)-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}-2- (methylamino)propyl N-[(benzylamino)carbonyl]-3-[(1- propylbutyl)sulfonyl]alaninate 1550 4-{[(1R,2S)-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}-2- (methylamino)propyl]oxy}-4-oxo-3-{[(1-propylbutyl)sulfonyl]methyl}butanoic acid 1552 4-[((1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3- phenylpropyl)oxy]-3-{[(3-methylbutyl)sulfonyl]methyl}-4-oxobutanoic acid 1554 1-((1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl) 4- methyl 2-{[(3-methylbutyl)sulfonyl]methyl}succinate 1556 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 4- amino-2-{[(3-methylbutyl)sulfonyl]methyl}-4-oxobutanoate 1558 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 4- (methylamino)-2-{[(3-methylbutyl)sulfonyl]methyl}-4-oxobutanoate 1560 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 4- (dimethylamino)-2-{[(3-methylbutyl)sulfonyl]methyl}-4-oxobutanoate 1562 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)- 2-{[(1-propylbutyl)sulfonyl]methyl}propanoate 1564 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)- 2-{[(1-propylbutyl)sulfonyl]methyl}propanoate 1566 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)- 2-{[(1-propylbutyl)sulfonyl]methyl}propanoate 1568 (1R,2R)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 3- (ethylsulfonyl)-2-{[(isobutylsulfonyl)amino]methyl}propanoate 1570 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 3- (ethylthio)-2-{[(isobutylsulfonyl)amino]methyl}propanoate 1572 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2S)-2- {[(3-methylbutyl)sulfonyl]amino}-4-(methylsulfonyl)butanoate 1574 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl N-[(3- methylbutyl)sulfonyl]-L-methioninate 1576 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 3- (acetylthio)-2-{[(3-methylbutyl)sulfonyl]methyl}propanoate 1578 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl)-3-phenylpropyl 2- hydroxy-3-[(1-propylbutyl)sulfonyl]propanoate 1580 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 2- hydroxy-3-[(3-methylbutyl)sulfonyl]propanoate 1582 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 2- hydroxy-3-[(3-methoxyphenyl)sulfonyl]propanoate 1584 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 2-hydroxy-4-(phenylsulfonyl)butanoate 1586 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 2- hydroxy-4-[(3-methylbutyl)sulfonyl]butanoate 1588 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 4-[(3- methylbutyl)sulfonyl]-2-phenoxybutanoate 1590 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 2-(3- methoxyphenoxy)-4-[(3-methylbutyl)sulfonyl]butanoate 1592 3-{1-{[((1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3- phenylpropyl)oxy]carbonyl}-3-[(3-methylbutyl)sulfonyl]propoxy}benzoic acid 1594 methyl 3-{1-{[((1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3- phenylpropyl)oxy]carbonyl}-3-[(3-methylbutyl)sulfonyl]propoxy}benzoate 1596 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 2- hydroxy-4-(phenylsulfonyl)butanoate 1598 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 2- hydroxy-4-(phenylthio)butanoate 1600 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 2- methoxy-4-(phenylsulfonyl)butanoate 1602 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 2- methoxy-4-(phenylthio)butanoate 1604 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 4- (phenylsulfonyl)-2-propoxybutanoate 1606 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 2- (benzyloxy)-4-(phenylsulfonyl)butanoate 1608 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl N- [(benzyloxy)carbonyl]methioninate 1610 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2S)-2- amino-5-oxo-5-piperidin-1-ylpentanoate 1612 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2S)-2- [(2-methoxy-2-oxoethyl)amino]-5-oxo-5-piperidin-1-ylpentanote 1614 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2R)-2- amino-5-oxo-5-piperidin-1-yllpentanoate 1616 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2R)-2- [(2-ethoxy-2-oxoethyl)amino]-5-oxo-5-piperidin-1-ylpentanoate 1618 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2R)-2- [(4-ethoxy-4-oxobutyl)amino]-5-oxo-5-piperidin-1-ylpentanoate 1620 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino)methyl}propyl (2R)-2-[(methoxycarbonyl)amino]-4- oxooctanoate 1622 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-butyl-N-(methoxycarbonyl)-D-homoserinate 1624 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(2-butyl-1,3-dioxolan-2-yl)-N- (methoxycarbonyl)-D-alaninate 1626 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(2-butyl-1,3-dioxan-2-yl)-N- (methoxycarbonyl)-D-alaninate 1628 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2R)-4,4-difluoro-2- [(methoxycarbonyl)amino]octanoate 1630 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2R)-4-fluoro-2- [(methoxycarbonyl)amino]octanoate 1632 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino)methyl)}propyl (2R)-2-[(methoxycarbonyl)amino]-5- oxononanoate 1634 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2R)-5-hydroxy-2- [(methoxycarbonyl)amino]nonanoate 1636 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2R)-4-(2-butyl-1,3-dioxolan-2-yl)-2- [(methoxycarbonyl)amino]butanoate 1638 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2R)-4-(2-butyl-1,3-dioxan-2-yl)-2- [(methoxycarbonyl)amino]butanoate 1640 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2R)-5-fluoro-2- [(methoxycarbonyl)amino]nonanoate 1642 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2R)-5,5-difluoro-2- [(methoxycarbonyl)amino]nonanoate 1644 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethynylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-(methoxycarbonyl)-D- alaninate 1646 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3- (trifluoromethyl)benzyl]amino}methyl)propyl 3-(butylsulfonyl)-N- (methoxycarbonyl)-D-alaninate 1648 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethylphenyl)cyclopropyl]amino}methyl)propyl 3-(butylsulfonyl)-N- (methoxycarbonyl)-D-alaninate 1650 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethynylphenyl)cyclopropyl]amino}methyl)propyl 3-(butylsulfonyl)-N- (methoxycarbonyl)-D-alaninate 1652 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-[({1-[3- (trifluoromethyl)phenyl]cyclopropyl}amino)methyl]propyl 3-(butylsulfonyl)-N- (methoxycarbonyl)-D-alaninate 1654 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethynylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-[(3-methyl-1H-pyrazol- 5-yl)carbonyl]-D-alaninate 1656 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3- (trifluoromethyl)benzyl]amino}methyl)propyl 3-(butylsulfonyl)-N-[(3-methyl- 1H-pyrazol-5-yl)carbonyl]-D-alaninate 1658 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethylphenyl)cyclopropyl]amino}methyl)propyl 3-(butylsulfonyl)-N-[(3-methyl- 1H-pyrazol-5-yl)carbonyl]-D-alaninate 1660 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethynylphenyl)cyclopropyl]amino}methyl)propyl 3-(butylsulfonyl)-N-[(3- methyl-1H-pyrazol-5-yl)carbonyl]-D-alaninate 1662 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-[({1-[3- (trifluoromethyl)phenyl]cyclopropyl}amino)methyl]propyl 3-(butylsulfonyl)-N- [(3-methyl-1H-pyrazol-5-yl)carbonyl]-D-alaninate 1664 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2R)-2-{[(methylamino)carbonyl]amino}-4- oxooctanoate 1666 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 4-butyl-N-[(methylamino)carbonyl]-D- homoserinate 1668 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(2-butyl-1,3-dioxolan-2-yl)-N- [(methylamino)carbonyl]-D-alaninate 1670 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(2-butyl-1,3-dioxan-2-yl)-N- [(methylamino)carbonyl]-D-alaninate 1672 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2R)-4,4-difluoro-2- {[(methylamino)carbonyl]amino}octanoate 1674 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2R)-4-fluoro-2- {[(methylamino)carbonyl]amino}octanoate 1676 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2R)-2-{[(methylamino)carbonyl]amino}-5- oxononanoate 1678 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2R)-5-hydroxy-2- {[(methylamino)carbonyl]amino}nonanoate 1680 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2R)-4-(2-butyl-1,3-dioxolan-2-yl)-2- {[(methylamino)carbonyl]amino}butanoate 1682 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2R)-4-(2-butyl-1,3-dioxan-2-yl)-2- {[(methylamino)carbonyl]amino}butanoate 1684 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2R)-5-fluoro-2- {[(methylamino)carbonyl]amino}nonanoate 1686 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl (2R)-5,5-difluoro-2- {[(methylamino)carbonyl]amino}nonanoate 1688 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethynylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N- [(methylamino)carbonyl]-D-alaninate 1690 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3- (trifluoromethyl)benzyl]amino}methyl)propyl 3-(butylsulfonyl)-N- [(methylamino)carbonyl]-D-alaninate 1692 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethylphenyl)cyclopropyl]amino}methyl)propyl 3-(butylsulfonyl)-N- [(methylamino)carbonyl]-D-alaninate 1694 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethynylphenyl)cyclopropyl]amino}methyl)propyl 3-(butylsulfonyl)-N- [(methylamino)carbonyl]-D-alaninate 1696 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-[({1-[3- (trifluoromethyl)phenyl]cyclopropyl}amino)methyl]propyl 3-(butylsulfonyl)-N- [(methylamino)carbonyl]-D-alaninate 1698 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethynylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-[(4-methyl-1H-pyrazol- 1-yl)carbonyl]-D-alaninate 1700 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3- (trifluoromethyl)benzyl]amino}methyl)propyl 3-(butylsulfonyl)-N-[(4-methyl- 1H-pyrazol-1-yl)carbonyl]-D-alaninate 1702 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethylphenyl)cyclopropyl]amino}methyl)propyl 3-(butylsulfonyl)-N-[(4-methyl- 1H-pyrazol-1-yl)carbonyl]-D-alaninate 1704 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3- ethynylphenyl)cyclopropyl]amino}methyl)propyl 3-(butylsulfonyl)-N-[(4- methyl-1H-pyrazol-1-yl)carbonyl]-D-alaninate 1706 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-[({1-[3- (trifluoromethyl)phenyl]cyclopropyl}amino)methyl]propyl 3-(butylsulfonyl)-N- [(4-methyl-1H-pyrazol-1-yl)carbonyl]-D-alaninate 1173

1175

1177

1179

1181

1183

1185

1187

1189

1191

1193

1195

1197

1199

1201

1203

1205

1207

1209

1211

1213

1215

1217

1219

1221

1223

1225

1227

1229

1231

1233 benzyl [(1R)-1-{[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]carbonyl}-3-(methylsulfonyl)propyl]carbamate 1235

1237

1239

1241

1243

1245

1247

1249

1251

1253

1255

1257

1259

1261

1263

1265

1267

1269

1271

1273

1275

1277

1279

1281

1283

1285

1287

1289

1291

1293

1295

1297

1299 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-[(tetrahydro- 2H-pyran-4-yloxy)carbonyl]alaninate 1301

1303 S-(3-[[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](3-methoxybenzyl)amino]-2- {[(3-methylbutyl)sulfonyl]methyl}-3-oxopropyl) ethanethioate 1305

1307

1309 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(3-methoxybenzyl)-2-(3- methoxyphenoxy)-4-[(3-methylbutyl)sulfonyl]butanamide 1311

1313

1315

1317

1319

1321

N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(butylsulfonyl)-N¹-(3-ethylbenzyl)-N²-(3,3,3-trifluoropropanoyl)-D-alaninamide 1323

N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(butylsulfonyl)-N¹-(3-ethylbenzyl)-N²-(trifluoroacetyl)-D-alaninamide 1325

N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-2-methoxy-N-(3-methoxy-benzyl)-4-(phenylthio)butanamide 1327

1329

N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(butylsulfonyl)-N²-(cyclopropylcarbonyl)-N¹-(3-ethylbenzyl)-D-alaninamide 1331 β-alanyl-N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3- (butylsulfonyl)-N¹-(3-ethylbenzyl)-D-alaninamide 1333 glycyl-N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3- (butylsulfonyl)-N¹-(3-ethylbenzyl)-D-alaninamide 1335 (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2R)-2- [(4-ethoxy-4-oxobutyl)amino]-5-oxo-5-piperidin-1-ylpentanoate 1337 N,N-dimethyl-β-alanyl-N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2- hydroxybutyl]-3-(butylsulfonyl)-N¹-(3-ethylbenzyl-D-alaninamide 1339 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(butylsulfonyl)- N¹-(3-ethylbenzyl)-N²-(methoxyacetyl)-D-alaninamide 1341

1343

1345 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(2-butyl-1,3-dioxan-2-yl)-N- (methoxycarbonyl)-D-alaninate 1347

1349

1351

1353

1355

1357

N²-acetyl-N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(butylsulfonyl)-N¹-(3-methylbutyl)-D-alaninamide 1359

N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-cyclopropyl-N²-(cyclopropylcarbonyl)-3-[(1-propylbutyl)sulfonyl]-D-alaninamide 1361

N²-acetyl-N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3-methylbutyl)-3-[(1-propylbutyl)sulfonyl]D-alaninamide 1363

1365

1367

1369

1371

1373

N-phenylglycyl-N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]-D-alaninamide 1375

1377

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1381

1383

1385 N-acetyl-β-alanyl-N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2- hydroxybutyl]-N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]-D-alaninamide 1387 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N²-(chloroacetyl)- N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]-D-alaninamide 1389 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3- ethylbenzyl)-N²-(methoxyacetyl)-3-[(1-propylbutyl)sulfonyl]-D-alaninamide 1391 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3- ethylbenzyl)-N²-(3-methoxypropanoyl)-3-[(1-propylbutyl)sulfonyl]-D- alaninamide 1393 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N²-(2,2- dimethylpropanoyl)-N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]-D- alaninamide 1395 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3- ethylbenzyl)-N²-isobutyryl-3-[(1-propylbutyl)sulfonyl]-D-alaninamide 1397

1399

N²-acetyl-N¹-[(2R,3S)-3-amino-4-(3,5-difluoro-phenyl)-2-hydroxybutyl]-N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]-D-alaninamide 1401

1403

1405

1407

1409

1411

N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N²-(cyclopropylcarbonyl)-N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]-D-alaninamide 1413

N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3-ethylbenzyl)-N²-propionyl-3-[(1-propylbutyl)sulfonyl]-D-alaninamide 1415

1417

1419

1421

1423

5-oxo-D-prolyl-N¹-[(2R,3S)-3-amino-4-(3,5-difluoro-phenyl)-2-hydroxybutyl]-N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]alaninamidehydrochloride 1425

5-oxo-L-prolyl-N¹-[(2R,3S)-3-amino-4-(3,5-difluoro-phenyl)-2-hydroxybutyl]-N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]alaninamide 1427

N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxy-butyl]-N¹-(3-ethylbenzyl)-N²-[3-(4-oxo-2-thioxo-1,3-thiazolidin-3-yl)propanoyl]-3-[(1-propylbutyl)sulfonyl]alaninamide 1429

1431

1433

1435

1437

1439

1441

1443

N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxy-butyl]-N¹-(3-ethylbenzyl)-N²-(1H-imidazol-4-ylacetyl)-3-[(1-propylbutyl)sulfonyl]alaninamide 1445

1447

1449

1451

1453

1455

1457

1459

1461

1463

1465

1467

1469

1471

1473

1475

1477

1479

1481

1483

1485 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3- ethylbenzyl)-N²-(phenylacetyl)-3-[(1-propylbutyl)sulfonyl]alaninamide 1487 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3- ethylbenzyl)-N²-(3-phenylpropanoyl)-3-[(1-propylbutyl)sulfonyl]alaninamide 1489 N-(3-[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]-3-oxo-2-{[(1- propylbutyl)sulfonyl]methyl}propyl)benzamide 1491 N¹-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N²-(cyclopropylacetyl)-N¹-(3- methoxybenzyl)-3-[(1-propylbutyl)sulfonyl]alaninamide 1493 N¹-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N¹-(3-methoxybenzyl)-N²- [(methylsulfonyl)acetyl]-3-[(1-propylbutyl)sulfonyl]alaninamide 1495 N¹-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N¹-(3-methoxybenzyl)-N²- [(methylthio)acetyl]-3-[(1-propylbutyl)sulfonyl]alaninamide 1497

1499

1501

1503 N-(methylsulfonyl)glycyl-N¹-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N¹-(3- methoxybenzyl)-3-[(1-propylbutyl)sulfonyl]alaninamide 1505 N²-acetyl-N¹-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N¹-(3- methoxybenzyl)-3-(phenylsulfonyl)alaninamide 1507

1509

1511

1513

1515

1517

1519 2-[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]-1-[(butylsulfonyl)methyl]-2-oxoethyl acetate 1521 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-S-butyl-N¹-(3- ethylbenzyl)-D-cysteinamide 1523 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl)-3-(butylsulfinyl)- N¹-(3-ethylbenzyl)-D-alaninamide 1525 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(butylsulfonyl)- N¹-(3-ethylbenzyl)-D-alaninamide 1527 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(butylsulfonyl)- N¹-(3-ethylbenzyl)-L-alaninamide 1529 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(butylsulfonyl)- N¹-(3-methylbutyl)-D-alaninamide 1531 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-[1-(3- ethylphenyl)cyclopropyl]-3-[(1-propylbutyl)sulfonyl]-D-alaninamide 1533 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3- ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]-L-alaninamide 1535 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-cyclopropyl-3- [(1-propylbutyl)sulfonyl]-D-alaninamide 1537 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl)-N¹-(3- methylbutyl)-3-[(1-propylbutyl)sulfonyl]-D-alaninamide 1539 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3- ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]-D-alaninamide 1541 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3- ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]alaninamide 1543 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3- ethylbenzyl)-N²-(phenoxyacetyl)-3-[(1-propylbutyl)sulfonyl]alaninamide 1545 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N²-{[(5-chloro-2- thienyl)thio]peroxy}-N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]alaninamide 1547 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3- ethylbenzyl)-N²-(phenylsulfonyl)-3-[(1-propylbutyl)sulfonyl]alaninamide 1549 N²-[(benzylamino)carbonyl]-N¹-[(2R,3S)-4-(3,5-difluorophenyl)-2-hydroxy-3- (methylamino)butyl]-N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]alaninamide 1551 4-[[(2R,3S)-4-(3,5-difluorophenyl)-2-hydroxy-3-(methylamino)butyl](3- ethylbenzyl)amino]-4-oxo-3-{[(1-propylbutyl)sulfonyl]methyl}butanoic acid 1553 4-[[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](3-methoxybenzyl)amino]-3-{[(3- methylbutyl)sulfonyl]methyl}-4-oxobutanoic acid 1555 methyl 4-[[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](3- methoxybenzyl)amino]-3-{[(3-methylbutyl)sulfonyl]methyl}-4-oxobutanoate 1557 N¹-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N¹-(3-methoxybenzyl)-2-{[(3- methylbutyl)sulfonyl)methyl}succinamide 1559 N¹-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N¹-(3-methoxybenzyl)-N⁴- methyl-2-{[(3-methylbutyl)sulfonyl]methyl}succinamide 1561 N¹-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N¹-(3-methoxybenzyl)-N⁴,N⁴- dimethyl-2-{[(3-methylbutyl)sulfonyl]methyl}succinamide 1563 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(4,4-dimethyl- 2,5-dioxoimidazolidin-1-yl)-N-(3-ethylbenzyl)-2-{[(1- propylbutyl)sulfonyl]methyl}propanamide 1565 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(4,4-dimethyl- 2,5-dioxoimidazolidin-1-yl)-N-(3-ethylbenzyl)-2-{[(1- propylbutyl)sulfonyl]methyl}propanamide 1567 (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3- ethylbenzyl)amino]methyl}propyl 3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)- 2-{[(1-propylbutyl)sulfonyl]methyl}propanoate 1569 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3-(ethylsulfonyl)-2- {[(isobutylsulfonyl)amino]methyl}-N-(3-methoxybenzyl)propanamide 1571 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3-(ethylthio)-2- {[(isobutylsulfonyl)amino]methyl}-N-(3-methoxybenzyl)propanamide 1573 (2S)-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(3-methoxybenzyl)-2- {[(3-methylbutyl)sulfonyl]amino}-4-(methylsulfonyl)butanamide 1575 N¹-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N¹-(3-methoxybenzyl)-N²-[(3- methylbutyl)sulfonyl]-L-methioninamide 1577 S-(3-[[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](3-methoxybenzyl)amino]-2- {[(3-methylbutyl)sulfonyl]methyl}-3-oxopropyl) ethanethioate 1579 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-2-hydroxy-N-(3- methoxybenzyl)-3-[(1-propylbutyl)sulfonyl]propanamide 1581 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-2-hydroxy-N-(3- methoxybenzyl)-3-[(3-methylbutyl)sulfonyl]propanamide 1583 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-2-hydroxy-N-(3- methoxybenzyl)-3-[(3-methoxyphenyl)sulfonyl]propanamide 1585 N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)- 2-hydroxy-4-(phenylsulfonyl)butanamide 1587 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-2-hydroxy-N-(3- methoxybenzyl)-4-[(3-methylbutyl)sulfonyl]butanamide 1589 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(3-methoxybenzyl)-4-[(3- methylbutyl)sulfonyl]-2-phenoxybutanamide 1591 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(3-methoxybenzyl)-2-(3- methoxyphenoxy)-4-[(3-methylbutyl)sulfonyl]butanamide 1593 3-{1-{[[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](3- methoxybenzyl)amino]carbonyl}-3-[(3-methylbutyl)sulfonyl]propoxy}benzoic acid 1595 methyl 3-{1-{[[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](3- methoxybenzyl)amino]carbonyl}-3-[(3-methylbutyl)sulfonyl]propoxy}benzoate 1597 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-2-hydroxy-N-(3- methoxybenzyl)-4-(phenylsulfonyl)butanamide 1599 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-2-hydroxy-N-(3- methoxybenzyl)-4-(phenylthio)butanamide 1601 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-2-methoxy-N-(3- methoxybenzyl)-4-(phenylsulfonyl)butanamide 1603 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-2-methoxy-N-(3- methoxybenzyl)-4-(phenylthio)butanamide 1605 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(3-methoxybenzyl)-4- (phenylsulfonyl)-2-propoxybutanamide 1607 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-2-(benzyloxy)-N-(3- methoxybenzyl)-4-(phenylsulfonyl)butanamide 1609

1611

(2S)-2-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenyl-butyl]-N-(3-methoxybenzyl)-5-oxo-5-piperidin-1-ylpentanamide 1613

1615

(2R)-2-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenyl-butyl]-N-(3-methoxybenzyl)-5-oxo-5-piperidin-1-ylpentanamide 1617

1619

1621

methyl ((1R)-1-{[[(2R,3S)-3-amino-4-(3,5-difluoro-phenyl)-2-hydroxybutyl](3-ethylbenzyl)amino]carbonyl}-3-oxoheptyl)carbamate 1623

1625

1627

1629 methyl ((1R)-1-{[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]carbonyl}-3,3-difluoroheptyl)carbamate 1631 methyl ((1R)-1-{[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]carbonyl}-3-fluoroheptyl)carbamate 1633 methyl ((1R)-1-{[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]carbonyl}-4-oxooctyl)carbamate 1635 methyl ((1R)-1-{[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]carbonyl}-4-hydroxyoctyl)carbamate 1637 methyl [(1R)-1-{[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]carbonyl}-3-(2-butyl-1,3-dioxolan-2-yl)propyl]carbamate 1639 methyl [(1R)-1-{[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]carbonyl}-3-(2-butyl-1,3-dioxan-2-yl)propyl]carbamate 1641 methyl ((1R)-1-{[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]carbonyl}-4-fluorooctyl)carbamate 1643 methyl ((1R)-1-{[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3- ethylbenzyl)amino]carbonyl}-4,4-difluorooctyl)carbamate 1645

1647

1649

1651

1653

1655

1657

1659

1661

1663

1665 (2R)-N-((2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- ethylbenzyl)-2-{[(methylamino)carbonyl]amino}-4-oxooctanamide 1667 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-butyl-N¹-(3- ethylbenzyl)-N²-[(methylamino)carbonyl]-D-homoserinamide 1669 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(2-butyl-1,3- dioxolan-2-yl)-N¹-(3-ethylbenzyl)-N²-[(methylamino)carbonyl]-D-alaninamide 1671 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(2-butyl-1,3- dioxan-2-yl)-N¹-(3-ethylbenzyl)-N²-[(methylamino)carbonyl]-D-alaninamide 1673 (2R)-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- ethylbenzyl)-4,4-difluoro-2-{[(methylamino)carbonyl]amino}octanamide 1675 (2R)-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- ethylbenzyl)-4-fluoro-2-{[(methylamino)carbonyl]amino}octanamide 1677 (2R)-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- ethylbenzyl)-2-{[(methylamino)carbonyl]amino 1-5-oxononanamide 1679 (2R)-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- ethylbenzyl)-5-hydroxy-2-{[(methylamino)carbonyl]aminol}nonanamide 1681 (2R)-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl)-4-(2-butyl- 1,3-dioxolan-2-yl)-N-(3-ethylbenzyl)-2- {[(methylamino)carbonyl]amino}butanamide 1683 (2R)-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-(2-butyl- 1,3-dioxan-2-yl)-N-(3-ethylbenzyl)-2- {[(methylamino)carbonyl]amino}butanamide 1685 (2R)-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- ethylbenzyl)-5-fluoro-2-{[(methylamino)carbonyl]amino}nonanamide 1687 (2R)-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3- ethylbenzyl)-5,5-difluoro-2-{[(methylamino)carbonyl]amino}nonanamide 1689 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(butylsulfonyl)- N¹-(3-ethynylbenzyl)-N²-[(methylamino)carbonyl]-D-alaninamide 1691 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(butylsulfonyl)- N²-[(methylamino)carbonyl]-N¹-[3-(trifluoromethyl)benzyl]-D-alaninamide 1693 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(butylsulfonyl)- N¹-[1-(3-ethylphenyl)cyclopropyl]-N²-[(methylamino)carbonyl]-D-alaninamide 1695 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(butylsulfonyl)- N¹-[1-(3-ethynylphenyl)cyclopropyl]-N²-[(methylamino)carbonyl]-D- alaninamide 1697 N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(butylsulfonyl)- N²-[(methylamino)carbonyl]-N¹-{1-[3-(trifluoromethyl)phenyl]cyclopropyl}-D- alaninamide 1699

1701

1703

1705

1707

1708

1709

1710

1711

1712

1713

1714

1715

1716

1717

1718

1719

1720

1721

1722

1723

1724

1725

1726

1727

1728

1729

REARRANGEMENT EXAMPLES

The following examples illustrate the acyl group migration that takes place with compounds of the invention. These examples are for illustration purposes, and are not intended to limit the scope of the invention.

General Procedure:

A compound of formula (I) OR (X) (5 mg) is dissolved in DMSO-d₆ (500 μL) and either pH 4 buffer solution (500 μL, potassium hydrogen phthalate buffer) or pH 7 buffer solution (500 μL, sodium and potassium phosphate buffer) is added. The sample is then heated to 40° C. The O-acyl or N-acyl to N-terminal N-acyl migration is monitored by observing the change in chemical shift for the aromatic fluorines using ¹⁹F-NMR. (Fluorine shifts associated with the desired migration were confirmed by spiking with authentic analogue). The sample is analyzed by ¹⁹F-NMR at approxiamately 0, 1.5, 3, 24, 48, and 144 hours. The amount of O-acyl pro-drug, N-acyl pro-drug, and desired migration product at each time point are assigned by integrating the corresponding NMR signal.

Example 1 Specific NMR Example

N˜1˜-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-(1,3-oxazol-2-yl)-N˜3˜,N˜3˜-dipropyl-N˜1˜-[3-(trifluoromethyl)benzyl]isophthalamide hydrochloride (PREPARATION 7, 5 mg) is dissolved in DMSO-d₆ (500 μL) and pH 4 buffer solution (500 μL, potassium hydrogen phthalate buffer) is added. The sample is then heated to 40° C. The N-acyl to N-terminal N-acyl migration is monitored by observing the change in chemical shift for the aromatic fluorines using ¹⁹F-NMR. (Fluorine shifts for the desired migration product in the presence of buffer was confirmed by spiking with authentic migration product, N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-5-(1,3-oxazol-2-yl)-N³,N³-dipropylisophthalamide.) NMR data is collected at 0, 1, 3, 25, 48, 96, and 144 hours. The amount of N-acyl pro-drug and desired migration product present at each time point is assigned by integrating the corresponding NMR signal. No migration to O-acyl pro-drug was observed using this method and was confirmed by spiking with authentic compound.

The following examples illustrate the solution acyl group migration of compounds of the formulae (I) and (X) as observed by ¹⁹F NMR spectroscopy. Data were collected as described in Example 1, above.

Example 2 Rearrangement of (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-ethynylphenyl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate (22)

Tables 1-2 provide relative concentrations as a funcation of time and at varying pH of prodrug 22 and its rearrangement product.

TABLE 1 Concentrations at 40° C., pH 7. pH 7, 40° C. HEA¹ TIME O-acyl pro-drug N-acyl prodrug product (hr) (% present) (% present) (% present) 0 100 0 0 0.5 10 0 10 1 0 0 100 ¹HEA = the hydroxyethylamine product of the acyl group migration.

TABLE 2 Concentrations at 40° C., pH 4. pH 4, 40° C. HEA TIME O-acyl pro-drug N-acyl prodrug product (hr) (% present) (% present) (% present) 0 100 0 0 0.5 93 0 7 1 87 0 13 3 66 0 27 6 49 0 42 24 9 0 78 48 0 0 86

Example 3 Rearrangement of (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-ethylphenyl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate dihydrochloride (17)

Tables 3-4 provide relative concentrations as a function of time and at varying pH of prodrug 17 and its rearrangement product.

TABLE 3 Concentrations at 40° C., pH 7. pH 7 40° C. HEA TIME O-acyl pro-drug N-acyl prodrug product (hr) (% present) (% present) (% present) 0 100 0 0 1.5 3 0 97 7 0 24 0 48 0 144 0

TABLE 4 Concentrations at 40° C., pH 4. pH 4 40° C. HEA TIME O-acyl pro-drug N-acyl prodrug product (hr) (% present) (% present) (% present) 0 100 0 0 1.5 53 0 47 3 33 0 67 6 11 0 89 24 0 0 100

Example 4 Rearrangement of N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N\(u)1\(d)-(3-ethylbenzyl)-5-(1,3-oxazol-2-yl)-N³,N³-dispropylisophthalamide hydrochloride (19)

Tables 5-6 provide relative concentrations as a function of time and at varying pH of prodrug 19 and its rearrangement product.

TABLE 5 Concentrations at 40° C., pH 7. pH 7 40° C. HEA TIME O-acyl pro-drug N-acyl prodrug product (hr) (% present) (% present) (% present) 0 0 100 0 1 0 97 3 3 0 91 9 24 0 60 40 48 0 37 63 96 0 19 81

TABLE 6 Concentrations at 40° C., pH 4. pH 4 40° C. HEA TIME O-acyl pro-drug N-acyl prodrug product (hr) (% present) (% present) (% present) 0 0 100 0 1 0 100 0 3 0 100 0 24 0 97 3 48 0 95 5 96 0 92 8

Example 5 Rearrangement of N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-(1,3-oxazol-2-yl)-N³,N³-dipropyl-N¹-[3-(trifluoromethyl)benzyl]-isophthalamide hydrochloride (20)

Tables 7-8 provide relative concentrations as a function of time and at varying pH of prodrug 20 and its rearrangement product.

TABLE 7 Concentrations at 40° C., pH 7. pH 7 40° C. HEA TIME O-acyl pro-drug N-acyl prodrug product (hr) (% present) (% present) (% present) 0 0 100 0 1 0 93 7 3 0 88 12 24 0 49 51 48 0 27 73 96 0 12 88

TABLE 8 Concentrations at 40° C., pH 4. pH 4 40° C. HEA TIME O-acyl pro-drug N-acyl prodrug product (hr) (% present) (% present) (% present) 0 0 100 0 1 0 97 3 3 0 96 4 24 0 93 7 48 0 92 8 96 0 88 12

Example 6 Rearrangement of (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(dispropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate dihydrochloride (16)

Tables 9-10 provide relative concentrations as a function of time and at varying pH of prodrug 16 and its rearrangement products.

TABLE 9 Concentrations at 40° C., pH 7. pH 7 40° C. HEA N-acyl prodrug product TIME O-acyl pro-drug (product A) (product B) (hr) (% present) (% present) (% present) 0 100 0 0 1.5 0 52 48 7 0 46 54 24 0 38 62 48 0 29 71 144 0 15 85

TABLE 10 Concentrations at 40° C., pH 4. pH 4 40° C. HEA N-acyl prodrug product TIME O-acyl pro-drug (product A) (product B) (hr) (% present) (% present) (% present) 0 100 0 0 1.5 33 13 54 3 9 15 76 24 0 12 88 48 0 12 88 144 0 9 91

Example 7 Rearrangement of (1R,2S)-2-amino-3-(3,5-uorophenyl)-1-({[3-(trifluoromethyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate dihydrochloride (18)

Tables 11-12 provide relative concentrations as a function of time and at varying pH of prodrug 18 and its rearrangement products.

TABLE 11 Concentrations at 40° C., pH 7. pH 7 40° C. O-acyl N-acyl prodrug HEA product TIME pro-drug (product A) (product B) (hr) (% present) (% present) (% present) 0 100 0 0 1.5 0 66 34 7 0 59 41 24 0 43 57 48 0 27 73 144 0 16 84

TABLE 12 Concentrations at 40° C., pH 4. pH 4 40° C. O-acyl N-acyl prodrug HEA product TIME pro-drug (product A) (product B) (hr) (% present) (% present) (% present) 0 100 0 0 1.5 32 14 54 3 8 18 74 30 0 21 79 54 0 20 80 126 0 14 86

BIOLOGY EXAMPLES Example A

Enzyme Inhibition Assay

The rearranged compounds of the invention are analyzed for inhibitory activity by use of the MBP-C125 assay. This assay determines the relative inhibition of beta-secretase cleavage of a model APP substrate, MBP-C125SW, by the compounds assayed as compared with an untreated control. A detailed description of the assay parameters can be found, for example, in U.S. Pat. No. 5,942,400. Briefly, the substrate is a fusion peptide formed of maltose binding protein (MBP) and the carboxy terminal 125 amino acids of APP-SW, the Swedish mutation. The beta-secretase enzyme is derived from human brain tissue as described in Sinha et al, 1999, Nature 40:537-540) or recombinantly produced as the full-length enzyme (amino acids 1-501), and can be prepared, for example, from 293 cells expressing the recombinant cDNA, as described in WO00/47618.

Inhibition of the enzyme is analyzed, for example, by immunoassay of the enzyme's cleavage products. One exemplary ELISA uses an anti-MBP capture antibody that is deposited on precoated and blocked 96-well high binding plates, followed by incubation with diluted enzyme reaction supernatant, incubation with a specific reporter antibody, for example, biotinylated anti-SW192 reporter antibody, and further incubation with streptavidin/alkaline phosphatase. In the assay, cleavage of the intact MBP-C125SW fusion protein results in the generation of a truncated amino-terminal fragment, exposing a new SW-192 antibody-positive epitope at the carboxy terminus. Detection is effected by a fluorescent substrate signal on cleavage by the phosphatase. ELISA only detects cleavage following Leu 596 at the substrate's APP-SW 751 mutation site.

Specific Assay Procedure:

Compounds are diluted in a 1:1 dilution series to a six-point concentration curve (two wells per concentration) in one 96-plate row per compound tested. Each of the test compounds is prepared in DMSO to make up a 10 millimolar stock solution. The stock solution is serially diluted in DMSO to obtain a final compound concentration of 200 micromolar at the high point of a 6-point dilution curve. Ten (10) microliters of each dilution is added to each of two wells on row C of a corresponding V-bottom plate to which 190 microliters of 52 millimolar NaOAc, 7.9% DMSO, pH 4.5 are pre-added. The NaoAc diluted compound plate is spun down to pellet precipitant and 20 microliters/well is transferred to a corresponding flat-bottom plate to which 30 microliters of ice-cold enzyme-substrate mixture (2.5 microliters MBP-C125SW substrate, 0.03 microliters enzyme and 24.5 microliters ice cold 0.09% TX100 per 30 microliters) is added. The final reaction mixture of 200 micromolar compound at the highest curve point is in 5% DMSO, 20 millimolar NaOAc, 0.06% TX100, at pH 4.5.

Warming the plates to 37 degrees C. starts the enzyme reaction. After 90 minutes at 37 degrees C., 200 microliters/well cold specimen diluent is added to stop the reaction and 20 microliters/well was transferred to a corresponding anti-MBP antibody coated ELISA plate for capture, containing 80 microliters/well specimen diluent. This reaction is incubated overnight at 4 degrees C. and the ELISA is developed the next day after a 2 hour incubation with anti-192SW antibody, followed by Streptavidin-AP conjugate and fluorescent substrate. The signal is read on a fluorescent plate reader.

Relative compound inhibition potency is determined by calculating the concentration of compound that showed a fifty percent reduction in detected signal (IC₅₀) compared to the enzyme reaction signal in the control wells with no added compound. In this assay, preferred compounds of the invention exhibit an IC₅₀ of less than 50 micromolar.

Example B

Cell Free Inhibition Assay Utilizing a Synthetic APP Substrate

A synthetic APP substrate that can be cleaved by beta-secretase and having N-terminal biotin and made fluorescent by the covalent attachment of Oregon green at the Cys residue is used to assay beta-secretase activity in the presence or absence of the inhibitory compounds of the invention. Useful substrates include the following:

Biotin-SEVNL-DAEFRC[oregon green]KK [SEQ ID NO: 1] Biotin-SEVKM-DAEFRC[oregon green]KK [SEQ ID NO: 2] Biotin-GLNIKTEEISEISY-EVEFRC[oregon green]KK [SEQ ID NO: 3] Biotin-ADRGLTTRPGSGLTNIKTEEISEVNL-DAEFRC[oregon green]KK [SEQ ID NO: 4] Biotin-FVNQHLCoxGSHLVEALY-LVCoxGERGFFYTPKAC[oregon green]KK [SEQ ID NO: 5]

The enzyme (0.1 nanomolar) and test compounds (0.001-100 micromolar) are incubated in pre-blocked, low affinity, black plates (384 well) at 37 degrees for 30 minutes. The reaction is initiated by addition of 150 millimolar substrate to a final volume of 30 microliter per well. The final assay conditions are: 0.001-100 micromolar compound inhibitor; 0.1 molar sodium acetate (pH 4.5); 150 nanomolar substrate; 0.1 nanomolar soluble beta-secretase; 0.001% Tween 20, and 2% DMSO. The assay mixture is incubated for 3 hours at 37 degrees C., and the reaction is terminated by the addition of a saturating concentration of immunopure streptavidin. After incubation with streptavidin at room temperature for 15 minutes, fluorescence polarization is measured, for example, using a LJL Acqurest (Ex485 nm/Em530 nm). The activity of the beta-secretase enzyme is detected by changes in the fluorescence polarization that occur when the substrate is cleaved by the enzyme. Incubation in the presence or absence of compound inhibitor demonstrates specific inhibition of beta-secretase enzymatic cleavage of its synthetic APP substrate. In this assay, preferred compounds of the invention exhibit an IC₅₀ of less than 50 micromolar.

Example C

Beta-Secretase Inhibition: P26-P4′SW Assay

Synthetic substrates containing the beta-secretase cleavage site of APP are used to assay beta-secretase activity, using the methods described, for example, in published PCT application WO00/47618. The P26-P4′SW substrate is a peptide of the sequence:

(biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNLDAEF [SEQ ID NO: 6]

The P26-P1 standard has the sequence:

(biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNL. [SEQ ID NO: 7]

Briefly, the biotin-coupled synthetic substrates are incubated at a concentration of from about 0 to about 200 micromolar in this assay. When testing inhibitory compounds, a substrate concentration of about 1.0 micromolar is preferred. Test compounds diluted in DMSO are added to the reaction mixture, with a final DMSO concentration of 5%. Controls also contain a final DMSO concentration of 5%. The concentration of beta secretase enzyme in the reaction is varied, to give product concentrations with the linear range of the ELISA assay, about 125 to 2000 picomolar, after dilution.

The reaction mixture also includes 20 millimolar sodium acetate, pH 4.5, 0.06% Triton X100, and is incubated at 37 degrees C. for about 1 to 3 hours. Samples are then diluted in assay buffer (for example, 145.4 nanomolar sodium chloride, 9.51 millimolar sodium phosphate, 7.7 millimolar sodium azide, 0.05% Triton X405, 6 g/liter bovine serum albumin, pH 7.4) to quench the reaction, then diluted further for immunoassay of the cleavage products.

Cleavage products can be assayed by ELISA. Diluted samples and standards are incubated in assay plates coated with capture antibody, for example, SW192, for about 24 hours at 4 degrees C. After washing in TTBS buffer (150 millimolar sodium chloride, 25 millimolar Tris, 0.05% Tween 20, pH 7.5), the samples are incubated with streptavidin-AP according to the manufacturer's instructions. After a one hour incubation at room temperature, the samples are washed in TTBS and incubated with fluorescent substrate solution A (31.2 g/liter 2-amino-2-methyl-1-propanol, 30 mg/liter, pH 9.5). Reaction with streptavidin-alkaline phosphate permits detection by fluorescence. Compounds that are effective inhibitors of beta-secretase activity demonstrate reduced cleavage of the substrate as compared to a control.

Example D

Assays Using Synthetic Oligopeptide-substrates

Synthetic oligopeptides are prepared that incorporate the known cleavage site of beta-secretase, and optionally detectable tags, such as fluorescent or chromogenic moieties. Examples of such peptides, as well as their production and detection methods are described in U.S. Pat. No. 5,942,400, herein incorporated by reference. Cleavage products can be detected using high performance liquid chromatography, or fluorescent or chromogenic detection methods appropriate to the peptide to be detected, according to methods well known in the art.

By way of example, one such peptide has the sequence SEVNL-DAEF [SEQ ID NO: 8], and the cleavage site is between residues 5 and 6. Another preferred substrate has the sequence ADRGLTTRPGSGLTNIKTEEISEVNL-DAEF [SEQ ID NO: 9], and the cleavage site is between residues 26 and 27.

These synthetic APP substrates are incubated in the presence of beta-secretase under conditions sufficient to result in beta-secretase mediated cleavage of the substrate. Comparison of the cleavage results in the presence of the compound inhibitor to control results provides a measure of the compound's inhibitory activity.

Example E

Inhibition of Beta-secretase Activity—Cellular Assay

An exemplary assay for the analysis of inhibition of beta-secretase activity utilizes the human embryonic kidney cell line HEKp293 (ATCC Accession No. CRL-1573) transfected with APP751 containing the naturally occurring double mutation Lys651Met52 to Asn651Leu652 (numbered for APP751), commonly called the Swedish mutation and shown to overproduce A beta (Citron et al., 1992, Nature 360:672-674), as described in U.S. Pat. No. 5,604,102.

The cells are incubated in the presence/absence of the inhibitory compound (diluted in DMSO) at the desired concentration, generally up to 10 micrograms/ml. At the end of the treatment period, conditioned media is analyzed for beta-secretase activity, for example, by analysis of cleavage fragments. A beta can be analyzed by immunoassay, using specific detection antibodies. The enzymatic activity is measured in the presence and absence of the compound inhibitors to demonstrate specific inhibition of beta-secretase mediated cleavage of APP substrate.

Example F

Inhibition of Beta-secretase in Animal Models of AD

Various animal models can be used to screen for inhibition of beta-secretase activity. Examples of animal models useful in the invention include, but are not limited to, mouse, guinea pig, dog, and the like. The animals used can be wild type, transgenic, or knockout models. In addition, mammalian models can express mutations in APP, such as APP695-SW and the like described herein. Examples of transgenic non-human mammalian models are described in U.S. Pat. Nos. 5,604,102, 5,912,410 and 5,811,633.

PDAPP mice, prepared as described in Games et al., 1995, Nature 373:523-527 are useful to analyze in vivo suppression of A beta release in the presence of putative inhibitory compounds. As described in U.S. Pat. No. 6,191,166, 4 month old PDAPP mice are administered compound formulated in vehicle, such as corn oil. The mice are dosed with compound (1-30 mg/ml; preferably 1-10 mg/ml). After time, e.g., 3-10 hours, the animals are sacrificed, and brains removed for analysis.

Transgenic animals are administered an amount of the compound inhibitor formulated in a carrier suitable for the chosen mode of administration. Control animals are untreated, treated with vehicle, or treated with an inactive compound. Administration can be acute, i.e., single dose or multiple doses in one day, or can be chronic, i.e., dosing is repeated daily for a period of days. Beginning at time 0, brain tissue or cerebral fluid is obtained from selected animals and analyzed for the presence of APP cleavage peptides, including A beta, for example, by immunoassay using specific antibodies for A beta detection. At the end of the test period, animals are sacrificed and brain tissue or cerebral fluid is analyzed for the presence of A beta and/or beta-amyloid plaques. The tissue is also analyzed for necrosis.

Animals administered the compound inhibitors of the invention are expected to demonstrate reduced A beta in brain tissues or cerebral fluids and reduced beta amyloid plaques in brain tissue, as compared with non-treated controls.

Example G

Inhibition of A Beta Production in Human Patients

Patients suffering from Alzheimer's Disease (AD) demonstrate an increased amount of A beta in the brain. AD patients are administered an amount of the compound inhibitor formulated in a carrier suitable for the chosen mode of administration. Administration is repeated daily for the duration of the test period. Beginning on day 0, cognitive and memory tests are performed, for example, once per month.

Patients administered the compound inhibitors are expected to demonstrate slowing or stabilization of disease progression as analyzed by changes in one or more of the following disease parameters: A beta present in CSF or plasma; brain or hippocampal volume; A beta deposits in the brain; amyloid plaque in the brain; and scores for cognitive and memory function, as compared with control, non-treated patients.

Example H

Prevention of a Beta Production in Patients at Risk for AD

Patients predisposed or at risk for developing AD are identified either by recognition of a familial inheritance pattern, for example, presence of the Swedish Mutation, and/or by monitoring diagnostic parameters. Patients identified as predisposed or at risk for developing AD are administered an amount of the compound inhibitor formulated in a carrier suitable for the chosen mode of administration. Administration is repeated daily for the duration of the test period. Beginning on day 0, cognitive and memory tests are performed, for example, once per month.

Patients administered the compound inhibitors are expected to demonstrate slowing or stabilization of disease progression as analyzed by changes in one or more of the following disease parameters: A beta present in CSF or plasma; brain or hippocampal volume; amyloid plaque in the brain; and scores for cognitive and memory function, as compared with control, non-treated patients.

The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention. 

1. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein one of R_(N) and R_(N)′ is hydrogen and the other is C(═O)—(CRR′)₀₋₆R₁₀₀, —C(═O)—(CRR′)₁₋₆—O—R′₁₀₀, —C(═O)—(CRR′)₁₋₆—S—R′₁₀₀, —C(═O)—(CRR′)₁₋₆-C(═O)—R₁₀₀, —C(═O)—(CRR′)₁₋₆—SO₂—R₁₀₀, —C(═O)—(CRR′)₁₋₆—NR₁₀₀—R′₁₀₀, or

wherein R₄ is selected from the group consisting of H; NH₂; —NH—(CH₂)_(n6)—R₄₋₁; —NHR₈; —NR₅₀C(O)R₅; C₁-C₄ alkyl-NHC(O) R₅; —(CH₂)₀₋₄R₈; —O—C₁-C₄ alkanoyl; OH; C₆-C₁₀ aryloxy optionally substituted with 1, 2, or 3 groups that are independently halogen, C₁-C₄ alkyl, —CO₂H, —C(O)—C₁-C₄ alkoxy, or C₁-C₄ alkoxy; C₁-C₆ alkoxy; aryl C₁-C₄ alkoxy; —NR₅₀CO₂R₅₁; —C₁-C₄ alkyl-NR₅₀CO₂R₅₁; —C≡N; —CF₃; —CF₂—CF₃; —C≡CH; —CH₂—CH═CH₂; —(CH₂)₁₋₄—R₄₋₁; —(CH₂)₁₋₄—NH—R₄₋₁; —O—(CH₂)_(n6)—R₄₋₁; —S—(CH₂)_(n6)—R₄₋₁; —(CH₂)₀₋₄NHC(O)—(CH₂)₀₋₆—R₅₂; —(CH₂)₀₋₄—R₅₃—(CH₂)₀₋₄—R₅₄; wherein n₆ is 0, 1, 2, or 3; n₇ is 0, 1, 2, or 3; R₄₋₁ is selected from the group consisting of —SO₂—(C₁-C₈ alkyl), —SO—(C₁-C₈ alkyl), —S—(C₁-C₈ alkyl), —S—CO—(C₁-C₆ alkyl), —SO₂—NR₄₋₂R₄₋₃; —CO—C₁-C₂ alkyl; —CO—NR₄₋₃R₄₋₄; R₄₋₂ and R₄₋₃ are independently H, C₁-C₃ alkyl, or C₃-C₆ cycloalkyl; R₄₋₄ is alkyl, arylalkyl, alkanoyl, or arylalkanoyl; R₄₋₆ is —H or C₁-C₆ alkyl; R₅ is selected from the group consisting of C₃-C₇ cycloalkyl; C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, —NR₆R₇, C₁-C₄ alkoxy, C₅-C₆ heterocycloalkyl, C₅-C₆ heteroaryl, C₆-C₁₀ aryl, C₃-C₇ cycloalkyl C₁-C₄ alkyl, —S—C₁-C₄ alkyl, —SO₂—C₁-C₄ alkyl, —CO₂H, —CONR₆R₇, —CO₂—C₁-C₄ alkyl, C₆-C₁₀ aryloxy; heteroaryl optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₁-C₄ haloalkyl, or OH; heterocycloalkyl optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, or C₂-C₄ alkanoyl; aryl optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₁-C₄ haloalkyl; and —NR₆R₇; wherein R₆ and R₇ are independently selected from the group consisting of H, C₁-C₆ alkyl, C₂-C₆ alkanoyl, phenyl, —SO₂—C₁-C₄ alkyl, phenyl C₁-C₄ alkyl; R₈ is selected from the group consisting of SO₂-heteroaryl, —SO₂-aryl, —SO₂-heterocycloalkyl, —SO₂—C₁-C₁₀ alkyl, —C(O)NHR₉, heterocycloalkyl, —S—C₁-C₆ alkyl, —S—C₂-C₄ alkanoyl, wherein R₉ is aryl C₁-C₄ alkyl, C₁-C₆ alkyl, or H; R₅₀ is H or C₁-C₆ alkyl; R₅₁ is selected from the group consisting of aryl C₁-C₄ alkyl; C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, cyano, heteroaryl, —NR₆R₇, —C(O)NR₆R₇, C₃-C₇ cycloalkyl, or —C₁-C₄ alkoxy; heterocycloalkyl optionally substituted with 1 or 2 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₂-C₄ alkanoyl, aryl C₁-C₄ alkyl, and —SO₂ C₁-C₄ alkyl; alkenyl; alkynyl; heteroaryl optionally substituted with 1, 2, or 3 groups that are independently OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl); heteroarylalkyl optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl); aryl; heterocycloalkyl; C₃-C₈ cycloalkyl; and cycloalkylalkyl; wherein the aryl; heterocycloalkyl, C₃-C₈ cycloalkyl, and cycloalkylalkyl groups are optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkanoyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, hydroxy, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ thioalkoxy, C₁-C₆ thioalkoxy C₁-C₆ alkyl, or C₁-C₆ alkoxy C₁-C₆ alkoxy; R₅₂ is heterocycloalkyl, heteroaryl, aryl, cycloalkyl, —S(O)₀₋₂—C₁-C₆ alkyl, CO₂H, —C(O)NH₂, —C(O)NH(alkyl), —C(O)N(alkyl) (alkyl), —CO₂-alkyl, —NHS(O)₀₋₂—C₁-C₆ alkyl, —N(alkyl)S(O)₀₋₂—C₁-C₆ alkyl, —S(O)₀₋₂-heteroaryl, —S(O)₀₋₂-aryl, —NH(arylalkyl), —N(alkyl) (arylalkyl), thioalkoxy, or alkoxy, each of which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, alkoxy, thioalkoxy, halogen, haloalkyl, haloalkoxy, alkanoyl, NO₂, CN, alkoxycarbonyl, or amino carbonyl; R₅₃ is absent, —O—, —C(O)—, —NH—, —N(alkyl)-, —NH—S(O)₀₋₂—, —N(alkyl)S(O)₀₋₂, —S(O)₀₋₂—NH—, —S(O)₀₋₂—N(alkyl)-, —NH—C(S)—, or —N(alkyl)-C(S)—; R₅₄ is heteroaryl, aryl, arylalkyl, heterocycloalkyl, CO₂H, —CO₂-alkyl, —C(O)NH(alkyl), —C(O)N(alkyl) (alkyl), —C(O)NH₂, C₁-C₈ alkyl, OH, aryloxy, alkoxy, arylalkoxy, NH₂, NH(alkyl), N(alkyl) (alkyl), or —C₁-C₆ alkyl-CO₂—C₁-C₆ alkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, alkoxy, CO₂H, —CO₂-alkyl, thioalkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkanoyl, NO₂, CN, alkoxycarbonyl, or aminocarbonyl; X is selected from the group consisting of —C₁-C₆ alkylidenyl optionally optionally substituted with 1, 2, or 3 methyl groups; and —NR₄₋₆—; or R₄ and R₄₋₆ combine to form —(CH₂)_(n10)—, wherein n₁₀ is 1, 2, 3, or 4; Z is selected from the group consisting of a bond; SO₂; SO; S; and C(O); Y is selected from the group consisting of H; C₁-C₄ haloalkyl; C₅-C₆ heterocycloalkyl; C₆-C₁₀ aryl; OH; —N(Y₁) (Y₂); C₁-C₁₀ alkyl optionally substituted with 1 thru 3 substituents which can-be the same or different and are selected from the group consisting of halogen, hydroxy, alkoxy, thioalkoxy, and haloalkoxy; C₃-C₈ cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from C₁-C₃ alkyl, and halogen; alkoxy; aryl optionally substituted with halogen, alkyl, alkoxy, CN or NO₂; arylalkyl optionally substituted with halogen, alkyl, alkoxy, CN or NO_(2;) wherein Y₁ and Y₂ are the same or different and are H; C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C₁-C₄ alkoxy, C₃-C₈ cycloalkyl, and OH; C₂-C₆ alkenyl; C₂-C₆ alkanoyl; phenyl; —SO₂—C₁-C₄ alkyl; phenyl C₁-C₄ alkyl; or C₃-C₈ cycloalkyl C₁-C₄ alkyl; or Y₁, Y₂ and the nitrogen to which they are attached form a ring selected from the group consisting of piperazinyl, piperidinyl, morpholinyl, and pyrolidinyl, wherein each ring is optionally substituted with 1, 2, 3, or 4 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, or halogen; R₁ is —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl), or C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, OH, ═O, —SH, C≡N, CF₃, —C₁-C₃ alkoxy, amino, mono- or dialkylamino, —N(R)C(O)R′—, —OC(═O)-amino and —OC(═O)-mono- or dialkylamino, or C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or dialkylamino, or aryl, heteroaryl, heterocyclyl, —C₁-C₆ alkyl-aryl, —C₁-C₆ alkyl-heteroaryl, or —C₁-C₆ alkyl-heterocyclyl, where the ring portions of each are optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, —OH, —SH, —C≡N, —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′, or —N(R)SO₂R′, —C(═O)—(C₁-C₄) alkyl, —SO₂-amino, —SO₂-mono- or dialkylamino, —C(═O)-amino, —C(═O)-mono- or dialkylamino, —SO₂—(C₁-C₄) alkyl, or —C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups which are independently a halogen, or C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, —C₁-C₆ alkyl and mono- or dialkylamino, or C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF₃, —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, or C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl and mono- or dialkylamino; and the heterocyclyl group is optionally further substituted with oxo; R and R′ independently are hydrogen or C₁-C₁₀ alkyl; R₂ is selected from the group consisting of H; C₁-C₆ alkyl, optionally substituted with 1, 2, or 3 substituents that are independently selected from the group consisting of C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b); wherein R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl; —(CH₂)₀₋₄-aryl; —(CH₂)₀₋₄-heteroaryl; C₂-C₆ alkenyl; C₂-C₆ alkynyl; —CONR_(N-2)R_(N-3); —SO₂NR_(N-2)R_(N-3); —CO₂H; and —CO₂—(C₁-C₄ alkyl); R₃ is selected from the group consisting of H; C₁-C₆ alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b); —(CH₂)₀₋₄-aryl; —(CH₂)₀₋₄-heteroaryl; C₂-C₆ alkenyl; C₂-C₆ alkynyl; —CO—NR_(N-2)R_(N-3); —SO₂—NR_(N-2)R_(N-3); —CO₂H; and —CO—O—(C₁-C₄ alkyl); or R₂, R₃ and the carbon to which they are attached form a carbocycle of three thru seven carbon atoms, wherein one carbon atom is optionally replaced by a group selected from —O—, —S—, —SO₂—, or —NR_(N-2)—; R_(C) is selected from the group consisting of C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of R₂₀₅, —OC═ONR₂₃₅R₂₄₀, —S(═O)₀₋₂(C₁-C₆ alkyl), —SH, —NR₂₃₅C═ONR₂₃₅R₂₄₀, —C≡ONR₂₃₅R₂₄₀, and —S(═O)₂NR₂₃₅R₂₄₀; —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl wherein the cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of R₂₀₅, —CO₂H, and —CO₂—(C₁-C₄ alkyl); —(CR₂₄₅R₂₅₀)₀₋₄-aryl; —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl; —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl; —(CR₂₄₅R₂₅₀)₀₋₄-aryl-heteroaryl; —(CR₂₄₅R₂₅₀)₀₋₄-aryl-heterocycloalkyl; —(CR₂₄₅R₂₅₀)₀₋₄-aryl-aryl; —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-aryl; —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heterocycloalkyl; —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heteroaryl; —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-heteroaryl; —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-heterocycloalkyl; —(CR₂₄₅R₂₅₀)₀₋₄-heterocycloalkyl-aryl; —[C(R₂₅₅) (R₂₆₀)]₁₋₃—CO—N—(R₂₅₅)₂; —CH(aryl)₂; —CH(heteroaryl)₂; —CH(heterocycloalkyl)₂; —CH(aryl) (heteroaryl); cyclopentyl, cyclohexyl, or cycloheptyl ring fused to aryl, heteroaryl, or heterocycloalkyl wherein one carbon of the cyclopentyl, cyclohexyl, or cycloheptyl is optionally replaced with NH, NR₂₁₅, O, or S(═O)₀₋₂, and wherein the cyclopentyl, cyclohexyl, or cycloheptyl group can be optionally substituted with 1 or 2 groups that are independently R₂₀₅ or ═O; —CO—NR₂₃₅R₂₄₀; —SO₂—(C₁-C₄ alkyl); C₂-C₁₀ alkenyl optionally substituted with 1, 2, or 3 R₂₀₅ groups; C₂-C₁₀ alkynyl optionally substituted with 1, 2, or 3 R₂₀₅ groups; —(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH)—(CH₂)₀₋₁-aryl; —(CH₂)₀₋₁—CHR_(C-6)—(CH₂)₀₋₁-heteroaryl; —CH(-aryl or -heteroaryl)-CO—O(C₁-C₄ alkyl); —CH(—CH₂—OH)—CH(OH)-phenyl-NO₂; (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-OH; —CH₂—NH—CH₂—CH (O—CH₂—CH₃)₂; —H; and —(CH₂)₀₋₆—C(═NR₂₃₅) (NR₂₃₅R₂₄₀); wherein each aryl is optionally substituted with 1, 2, or 3 R₂₀₀; each heteroaryl is optionally substituted with 1, 2, 3, or 4 R₂₀₀; each heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R₂₁₀; R₂₀₀ at each occurrence is independently selected from the group consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3 R₂₀₅ groups; OH; —NO₂; halogen; —CO₂H; C≡N; —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl); —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl); —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl); —(CH₂)₀₋₄—CO—(C₃-C₇ cycloalkyl); —(CH₂)₀₋₄—CO—aryl; —(CH₂)₀₋₄—CO-heteroaryl; —(CH₂)₀₋₄—CO-heterocycloalkyl; —(CH₂)₀₋₄—CO₂R₂₁₅; —(CH₂)₀₋₄—SO₂—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl); —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl); —(CH₂)₀₋₄—SO₂—(C₃-C₇ cycloalkyl); —(CH₂)₀₋₄—N(H or R₂₁₅)—CO₂R₂₁₅; —(CH₂)₀₋₄—N(H or R₂₁₅)—CO—N(R₂₁₅)₂; —(CH₂)₀₋₄—N—CS—N(R₂₁₅)₂; —(CH₂)₀₋₄—N(—H or R₂₁₅)—CO—R₂₂₀; —(CH₂)₀₋₄—NR₂₂₀R₂₂₅; —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl); —(CH₂)₀₋₄—O—P(O)—(OR₂₄₀)₂; —(CH₂)₀₋₄—O—CO—N(R₂₁₅)₂; —(CH₂)₀₋₄—O—CS—N(R₂₁₅)₂; —(CH₂)₀₋₄—O—(R₂₁₅)₂; —(CH₂)₀₋₄—O—(R₂₁₅)₂—COOH; —(CH₂)₀₋₄—S—(R₂₁₅)₂; —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally substituted with 1, 2, 3, or 5 —F); C₃-C₇ cycloalkyl; C₂-C₆ alkenyl optionally substituted with 1 or 2 R₂₀₅ groups; C₂-C₆ alkynyl optionally substituted with 1 or 2 R₂₀₅ groups; —(CH₂)₀₋₄—N(H or R₂₁₅)—SO₂—R₂₂₀; and —(CH₂)₀₋₄—C₃-C₇ cycloalkyl; wherein each aryl group at each occurrence is optionally substituted with 1, 2, or 3 groups that are independently R₂₀₅, R₂₁₀ or C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are independently R₂₀₅ or R₂₁₀; wherein each heterocycloalkyl group at each occurrence is optionally substituted with 1, 2, or 3 groups that are independently R₂₁₀; wherein each heteroaryl group at each occurrence is optionally substituted with 1, 2, or 3 groups that are independently R₂₀₅, R₂₁₀, or C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are independently R₂₀₅ or R₂₁₀; R₂₀₅ at each occurrence is independently selected from the group consisting of C₁-C₆ alkyl, halogen, —OH, —O-phenyl, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, NH₂, NH(C₁-C₆ alkyl), and N—(C₁-C₆ alkyl) (C₁-C₆ alkyl); R₂₁₀ at each occurrence is independently selected from the group consisting of C₁-C₆ alkyl optionally substituted with 1, 2, or 3 R₂₀₅ groups; C₂-C₆ alkenyl optionally substituted with 1, 2, or 3 R₂₀₅ groups; C₂-C₆ alkynyl optionally substituted with 1, 2, or 3 R₂₀₅ groups; halogen; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; —NR₂₂₀R₂₂₅; OH; C≡N; C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 R₂₀₅ groups; —CO—(C₁-C₄ alkyl); —SO₂NR₂₃₅R₂₄₀; —CO—NR₂₃₅R₂₄₀; —SO₂—(C₁-C₄ alkyl); and ═O; wherein R₂₁₅ at each occurrence is independently selected from the group consisting of C₁-C₆ alkyl, —(CH₂)₀₋₂-(aryl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, and —(CH₂)₀₋₂-(heteroaryl), —(CH₂)₀₋₂-(heterocycloalkyl); wherein the aryl group at each occurrence is optionally substituted with 1, 2, or 3 groups that are independently R₂₀₅ or R₂₁₀; wherein the heterocycloalkyl group at each occurrence is optionally substituted with 1, 2, or 3 R₂₁₀; wherein each heteroaryl group at each occurrence is optionally substituted with 1, 2, or 3 R₂₁₀; R₂₂₀and R₂₂₅ at each occurrence are independently selected from the group consisting of —H, —C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl, amino C₁-C₆ alkyl; halo C₁-C₆ alkyl; -C₃-C₇ cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl), —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁-C₆ alkyl chain with one double bond and one triple bond, -aryl, -heteroaryl, and -heterocycloalkyl; wherein the aryl group at each occurrence is optionally substituted with 1, 2, or 3 R₂₇₀ groups, wherein R₂₇₀ at each occurrence is independently R₂₀₅, C₁-C₆ alkyl optionally substituted with 1, 2, or 3 R₂₀₅ groups; C₂-C₆ alkenyl optionally substituted with 1, 2, or 3 R₂₀₅ groups; C₂-C₆ alkynyl optionally substituted with 1, 2, or 3 R₂₀₅ groups; halogen; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; NR₂₃₅R₂₄₀; OH; C≡N; C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 R₂₀₅ groups; —CO—(C₁-C₄ alkyl); —SO₂—NR₂₃₅R₂₄₀; —CO—NR₂₃₅R₂₄₀; —SO₂—(C₁-C₄ alkyl); and ═O; wherein the heterocycloalkyl group at each occurrence is optionally substituted with 1, 2, or 3 R₂₀₅ groups; wherein each heteroaryl group at each occurrence is optionally substituted with 1, 2, or 3 R₂₀₅ groups; R₂₃₅ and R₂₄₀ at each occurrence are independently H, or C₁-C₆ alkyl; R₂₄₅ and R₂₅₀ at each occurrence are independently selected from the group consisting of H, C₁-C₄ alkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl C₁-C₄ alkyl, heteroaryl C₁-C₄ alkyl, and phenyl; or R₂₄₅ and R₂₅₀ are taken together with the carbon to which they are attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon atoms, optionally where one carbon atom is replaced by a heteroatom selected from the group consisting of —O—, —S—, —SO₂—, and —NR₂₂₀—; R₂₅₅ and R₂₆₀ at each occurrence are independently selected from the group consisting of H; C₁-C₆ alkyl optionally substituted with 1, 2, or 3 R₂₀₅ groups; C₂-C₆ alkenyl optionally substituted with 1, 2, or 3 R₂₀₅ groups; C₂-C₆ alkynyl optionally substituted with 1, 2, or 3 R₂₀₅ groups; —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl); —(CH₂)₀₋₄—C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 R₂₀₅ groups; —(C₁-C₄ alkyl)-aryl; —(C₁-C₄ alkyl)-heteroaryl; —(C₂C₄ alkyl)-heterocycloalkyl; -aryl; -heteroaryl; -heterocycloalkyl; —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-aryl; —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heteroaryl; and; —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heterocycloalkyl; wherein R₂₆₅ at each occurrence is independently —O—, —S—or —N(C₁-C₆ alkyl)-; each aryl or phenyl is optionally substituted with 1, 2, or 3 groups that are independently R₂₀₅, R₂₁₀, or C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are independently R₂₀₅ or R₂₁₀; each heteroaryl is optionally substituted with 1, 2, 3, or 4 R₂₀₀, each heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R₂₁₀; R₁₀₀ and R′₁₀₀ independently represent aryl, heteroaryl, heterocyclyl, -aryl-W-aryl, -aryl-W-heteroaryl, -aryl-W-heterocyclyl, -heteroaryl-W-aryl, -heteroaryl-W-heteroaryl, -heteroaryl-W- heterocyclyl, -heterocyclyl-W-aryl, -heterocyclyl-W-heteroaryl, -heterocyclyl-W-heterocyclyl, —CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-aryl, —CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-heterocyclyl or —CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-heteroaryl, where the ring portions of each are optionally substituted with 1, 2, or 3 groups independently selected from —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃, —(CH₂)₀₋₄—O—P(═O) (OR) (OR′), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—O—(CH₂)₀₋₄CONR₁₀₂R₁₀₂′, —(CH₂)₀₋₄—CO—(C₁- C₁₂ alkyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂C₁₂ alkynyl), —(CH₂)₀₋₄—CO—(CH₂)₀₋₄(C₃C₇ cycloalkyl), —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀, —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₄₀, —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl), —(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—N (R₁₅₀)—CO—O—R₁₅₀, —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R150)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅, —(CH₂)₀₋₄—NR₁₅₀R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂, —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂—(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀), —(CH₂)₀₋₄—O—R₁₅₀′—COOH, —(CH₂)₀₋₄—S—(R₁₅₀), —(CH₂)₀₋₄—N(R₁₅₀)—SO₂R₁₀₅, —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, (C₂-C₁₀)alkenyl, and (C₂-C₁₀)alkynyl, or R₁₀₀ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 R₁₁₅ groups, or R₁₀₀ is —(C₁-C₆ alkyl)-O—C₁-C₆ alkyl) or —(C₁-C₆ alkyl)-S—(C₁-C₆ alkyl), each of which is optionally substituted with 1, 2, or 3 R₁₁₅ groups, or R₁₀₀ is C₃-C₈ cycloalkyl optionally substituted with 1, 2, or 3 R₁₁₅ groups; W is —(CH₂)₀₋₄, —O—, S(O)₀₋₂—, —N(R₁₃₅)—, —CR(OH)— or —C(O)—; R₁₀₂ and R₁₀₂′ independently are hydrogen, or C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, aryl or —R₁₁₀; R₁₀₅ and R′₁₀₅ independently represent —H, —R₁₁₀, —R₁₂₀, C₃-C₇ cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆ alkyl chain with one double bond and one triple bond, or C₁-C₆ alkyl optionally substituted with —OH or —NH₂; or, C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, or R₁₀₅ and R′₁₀₅ together with the atom to which they are attached form a 3 to 7 membered carbocylic ring, where one member is optionally a heteratom selected from —O—, —S(O)₀₋₂—, —N(R₁₃₅)—, the ring being optionally substituted with 1, 2 or 3 independently selected R₁₄₀ groups; R₁₁₅ at each occurrence is independently halogen, —OH, —CO₂R₁₀₂, —C₁-C₆ thioalkoxy, —CO₂-phenyl, —NR₁₅₀R′₁₃₅, —SO₂—(C₁-C₈ alkyl), —C(═O)R₁₈₀, R₁₈₀, —CONR₁₅₀R′₁₀₅, —SO₂NR₁₅₀R′₁₀₅, —NH—CO—(C₁-C₆ alkyl), —NH—C(═O)—OH, —NH—C(═O)—OR, —NH—C(═O)—O-phenyl, —O—C(═O)—(C₁-C₆ alkyl), —O—C(═O)-amino, —O—C(═O)-mono- or dialkylamino, —O—C(═O)-phenyl, —O—(C₁-C₆ alkyl)-CO₂H, —NH—SO₂—(C₁-C₆ alkyl), C₁-C₆ alkoxy or C₁-C₆ haloalkoxy; R₁₃₅ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, —(CH₂)₀₋₂-(aryl), —(CH₂)₀₋₂-(heteroaryl), or —(CH₂)₀₋₂-(heterocyclyl); R₁₄₀ is heterocyclyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl, and ═O; R₁₄₅ is C₁-C₆ alkyl or CF₃; R₁₅₀ is hydrogen, C₃-C₇ cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl with one double bond and one triple bond, —R₁₁₀, —R₁₂₀, or C₁-C₆ alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from —OH, —NH₂, C₁-C₃ alkoxy, R₁₁₀, and halogen; R₁₅₀′ is C₃-C₇ cycloalkyl, —(C₁-C₃ alkyl)-(C₃-C₇ cycloalkyl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl with one double bond and one triple bond, —R₁₁₀, —R₁₂₀, or C₁-C₆ alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from —OH, —NH₂, C₁-C₃ alkoxy, R₁₁₀, and halogen; R₁₅₅ is C₃-C₇ cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl with one double bond and one triple bond, —R₁₁₀, —R₁₂₀, or C₁-C₆ alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from —OH, —NH₂, C₁-C₃ alkoxy, and halogen; R₁₈₀ is selected from morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl, each of which is optionally substituted with 1, 2, 3, or 4 groups independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl, and ═O; R₁₁₀ is aryl optionally substituted with 1 or 2 R₁₂₅ groups; R₁₂₅ at each occurrence is independently halogen, amino, mono- or dialkylamino, —OH, —C≡N, —SO₂—NH₂, —SO₂—NH—C₁-C₆ alkyl, —SO₂—N(C₁-C₆ alkyl)₂, —SO₂—(C₁-C₄ alkyl), —CO—NH₂, —CO—NH—C₁-C₆ alkyl, or —CO—N(C₁-C₆ alkyl)₂, or C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently selected from C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- and dialkylamino, or C₁-C₆ alkoxy optionally substituted with one, two or three of halogen; R₁₂₀ is heteroaryl, which is optionally substituted with 1 or 2 R₁₂₅ groups; and R₁₃₀ is heterocyclyl optionally substituted with 1 or 2 R₁₂₅ groups wherein the compound comprises at least one heterocyclic or at least one heteroaryl group.
 2. A compound according to claim 1 wherein R_(N) is hydrogen.
 3. A compound according to claim 1 wherein R_(N)′ is hydrogen.
 4. A compound according to claim 1 wherein R₁ is —C₁-C₆ alkyl-aryl, —C₁-C₆ alkyl-heteroaryl, or —C₁-C₆ alkyl-heterocyclyl, where the ring portions of each are optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, —OH, —SH, —C≡N, —NO₂, —NR₁₅₀R′₁₀₅, —CO₂R, —N(R)COR′, or —N(R)SO₂R′, —C(═O)—(C₁-C₄) alkyl, —SO₂-amino, —SO₂-mono- or dialkylamino, —C(═O)-amino, —C(═O)-mono or dialkylamino, —SO₂—(C₁-C₄) alkyl, or C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups which are independently selected from halogen, or C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, —C₁-C₆ alkyl and mono- or dialkylamino, or C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF₃, —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, or C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl and mono- or dialkylamino; and the heterocyclyl group is optionally further substituted with oxo.
 5. A compound according to claim 1 wherein R₂ and R₃ are independently selected from H or C₁-C₆ alkyl optionally substituted with 1, 2, or 3 substituents selected from the group consisting of C₁-C₃ alkyl, halogen,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b).
 6. A compound according to claim 1 wherein R_(C) is —(CH₂₄₅R₂₅₀)₀₋₄-aryl, or —(CH₂₄₅R₂₅₀)₀₋₄-heteroaryl, wherein aryl and heteroaryl are optionally substituted with 1, 2, or 3 R₂₀₀ groups.
 7. A compound according to claim 2 wherein R_(N)′ is

wherein R₄ is NH₂; —NH—(CH₂)_(n6)—R₄₋₁; —NHR₈; —NR₅₀C(O)R₅; or —NR₅₀CO₂R₅₁; wherein n₆ is 0, 1, 2, or 3; n₇ is 0, 1, 2, or 3; R₄₋₁ is selected from the group consisting of —SO₂—(C₁-C₈ alkyl), —SO—(C₁-C₈ alkyl), —S—(C₁-C₈ alkyl), —S—CO—(C₁-C₆ alkyl), —SO₂—NR₄₋₂R₄₋₃; —CO—C₁-C₂ alkyl; —CO—NR₄₋₃R₄₋₄; R₄₋₂ and R₄₋₃ are independently H, C₁-C₃ alkyl, or C₃-C₆ cycloalkyl; R₄₋₄ is alkyl, phenylalkyl, C₂-C₄ alkanoyl, or phenylalkanoyl; R₅ is cyclopropyl; cyclobutyl; cyclopentyl; and cyclohexyl; wherein each cycloalkyl group is optionally substituted with one or two groups that are C₁-C₆ alkyl, more preferably C₁-C₂ alkyl, C₁-C₆ alkoxy, more preferably C₁-C₂ alkoxy, CF₃, OH, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl) (C₁-C₆ alkyl), halogen, CN, or NO₂; or the cycloalkyl group is substituted with 1 or 2 groups that are independently CF₃, Cl, F, methyl, ethyl or cyano; C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, —NR₆R₇, C₁-C₄ alkoxy, C₅-C₆ heterocycloalkyl, C₅-C₆ heteroaryl, phenyl, C₃-C₇ cycloalkyl, —S—C₁-C₄ alkyl, —SO₂—C₁-C₄ alkyl, —CO₂H, —CONR₆R₇, —CO₂—C₁-C₄ alkyl, or phenyloxy; heteroaryl optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₁-C₄ haloalkyl, or OH; heterocycloalkyl optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, or C₂-C₄ alkanoyl; phenyl optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₁-C₄ haloalkyl; and —NR₆R₇; wherein R₆ and R₇ are independently selected from the group consisting of H, C₁-C₆ alkyl, C₂-C₆ alkanoyl, phenyl, —SO₂—C₁-C₄ alkyl, and phenyl C₁-C₄ alkyl; R₈ is selected from the group consisting of SO₂-heteroaryl optionally substituted with 1 or 2 groups that are independently C₁-C₄ alkyl or halogen;, —SO₂-aryl, —SO₂-heterocycloalkyl, —C(O)NHR₉, heterocycloalkyl, —S—C₂-C₄ alkanoyl, wherein R₉ is phenyl C₁-C₄ alkyl, C₁-C₆ alkyl, or H; R₅₀ is H or C₁-C₆ alkyl; R₅₁ is selected from the group consisting of phenyl C₁-C₄ alkyl; C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, cyano, —NR₆R₇, —C(O)NR₆R₇, C₃-C₇ or —C₁-C₄ alkoxy; heterocycloalkyl optionally substituted with 1 or 2 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₂-C₄ alkanoyl, phenyl C₁-C₄ alkyl, and —SO₂ C₁-C₄ alkyl; heterocycloalkylalkyl optionally substituted with 1 or 2 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₂-C₄ alkanoyl, phenyl C₁-C₄ alkyl, and —SO₂ C₁-C₄ alkyl; alkenyl; alkynyl; heteroaryl optionally substituted with 1, 2, or 3 groups that are independently OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl); heteroarylalkyl optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl); phenyl; C₃-C₈ cycloalkyl, and cycloalkylalkyl, wherein the phenyl; C₃-C₈ cycloalkyl, and cycloalkylalkyl groups are optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkanoyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, hydroxy, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ thioalkoxy, C₁-C₆ thioalkoxy C₁-C₆ alkyl, or C₁-C₆ alkoxy C₁-C₆ alkoxy.
 8. A compound according to claim 3 wherein R_(N) is

wherein R₄ is NH₂; —NH—(CH₂)_(n6)—R₄; —NHR₈; —NR₅₀C(O)R₅; or —NR₅₀CO₂R₅₁; wherein n₆ is 0, 1, 2, or 3; n₇ is 0, 1, 2, or 3; R₄₋₁ is selected from the group consisting of —SO₂—(C₁-C₈ alkyl), —SO—(C₁-C₈ alkyl), —S—(C₁-C₈ alkyl), —S—CO—(C₁-C₆ alkyl), —SO₂—NR₄₋₂R₄₋₃; —CO—C₁-C₂ alkyl; —CO—NR₄₋₃R₄₋₄; R₄₋₂ and R₄₋₃ are independently H, C₁-C₃ alkyl, or C₃-C₆ cycloalkyl; R₄₋₄ is alkyl, phenylalkyl, C₂-C₄ alkanoyl, or phenylalkanoyl; R₅ is cyclopropyl; cyclobutyl; cyclopentyl; and cyclohexyl; wherein each cycloalkyl group is optionally substituted with one or two groups that are C₁-C₆ alkyl, more preferably C₁-C₂ alkyl, C₁-C₆ alkoxy, more preferably C₁-C₂ alkoxy, CF₃, OH, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl) (C₁-C₆ alkyl), halogen, CN, or NO₂; or the cycloalkyl group is substituted with 1 or 2 groups that are independently CF₃, Cl, F, methyl, ethyl or cyano; C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, —NR₆R₇, C₁-C₄ alkoxy, C₅-C₆ heterocycloalkyl, C₅-C₆ heteroaryl, phenyl, C₃-C₇ cycloalkyl, —S—C₁-C₄ alkyl, —SO₂—C₁-C₄ alkyl, —CO₂H, —CONR₆R₇, —CO₂—C₁-C₄ alkyl, or phenyloxy; heteroaryl optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₁-C₄ haloalkyl, or OH; heterocycloalkyl optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, or C₂-C₄ alkanoyl; phenyl optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₁-C₄ haloalkyl; and —NR₆R_(7;) wherein R₆ and R₇ are independently selected from the group consisting of H, C₁-C₆ alkyl, C₂-C₆ alkanoyl, phenyl, —SO₂—C₁-C₄ alkyl, and phenyl C₁-C₄ alkyl; R₈ is selected from the group consisting of SO₂-heteroaryl optionally substituted with 1 or 2 groups that are independently C₁-C₄ alkyl or halogen;, —SO₂-aryl, —SO₂-heterocycloalkyl, —C(O)NHR₉, heterocycloalkyl, —S—C₂-C₄ alkanoyl, wherein R₉ is phenyl C₁-C₄ alkyl, C₁-C₆ alkyl, or H; R₅₀ is H or C₁-C₆ alkyl; R₅₁ is selected from the group consisting of phenyl C₁-C₄ alkyl; C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, cyano, —NR₆R₇, —C(O)NR₆R₇, C₃-C₇ or —C₁-C₄ alkoxy; heterocycloalkyl optionally substituted with 1 or 2 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₂-C₄ alkanoyl, phenyl C₁-C₄ alkyl, and —SO₂ C₁-C₄ alkyl; heterocycloalkylalkyl optionally substituted with 1 or 2 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₂-C₄ alkanoyl, phenyl C₁-C₄ alkyl, and —SO₂ C₁-C₄ alkyl; alkenyl; alkynyl; heteroaryl optionally substituted with 1, 2, or 3 groups that are independently OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl); heteroarylalkyl optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl); phenyl; cycloalkyl, and cycloalkylalkyl, wherein the phenyl; C₃-C₈ cycloalkyl, and cycloalkylalkyl groups are optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkanoyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, hydroxy, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ thioalkoxy, C₁-C₆ thioalkoxy C₁-C₆ alkyl, or C₁-C₆ alkoxy C₁-C₆ alkoxy.
 9. A compound according to claim 2 wherein R_(N)′ is —C(═O)-phenyl, where the phenyl ring is optionally substituted with 1 or 2 groups independently selected from C₁-C₆ alkyl, halogen, —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—O—CO—N (R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, —(CH₂)₀₋₄—SO₂—NR₁₅₀R′₁₀₅, C₃-C₇ cycloalkyl, (C₂-C₁₀)alkenyl, —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀, or (C₂-C₁₀)alkynyl.
 10. A compound according to claim 3 wherein R_(N) is —C(═O)-phenyl, where the phenyl ring is optionally substituted with 1 or 2 groups independently selected from C₁-C₆ alkyl, halogen, —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—SO₂R₁₀₅, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅, C₃-C₇ cycloalkyl, (C₂-C₁₀)alkenyl, —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄R₁₃₀, or (C₂-C₁₀)alkynyl.
 11. A compound according to claim 1 selected from the group consisting of: N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-[(methylsulfonyl)amino]-1,3-thiazole-5-carboxamide (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl) amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate dihydrochloride (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-ethylphenyl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate dihydrochloride (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(trifluoromethyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate dihydrochloride N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N\(u)1\(d)-(3-ethylbenzyl)-5-(1,3-oxazol-2-yl) N³,N³-dipropylisophthalamide hydrochloride N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-(1,3-oxazol-2-yl)-N³,N³-dipropyl-N¹-[3-(trifluoromethyl)benzyl]isophthalamide hydrochloride N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-(1,3-oxazol-2-yl)-N³,N³-dipropyl-N¹-[3-(trifluoromethyl)benzyl]isophthalamide (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-ethynylphenyl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate (1R,2S)-2amino-3-(3,5-difluorophenyl)-1-({[(2-isobutyl-1,3-thiazol-5-yl)methyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-ethynylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-isopropylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate (1R,2S)-2amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-(4-methyl-1,3-oxazol-2-yl)benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(2isobutyl-1,3-thiazol-5-yl)methyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(3-isobutylisoxazol-5-yl)methyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-ethynylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate hydrochloride (1R,2S)-2amino-3-(3,5difluorophenyl)-1-({[3-(5-formyl-2-thienyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2amino-3-(3,5difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-{[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}-5-methylbenzoate hydrochloride (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl}benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethynylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate (1R,2S)-2-amino-3-(3,5difluorophenyl)-1-({[3-(3-thienyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(trifluoromethyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-(piperazin-1-ylsulfonyl)benzoate dihydrochloride (1R,2S)-2-amino-3 (3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-(3-methylisoxazol-4-yl)benzoate hydrochloride (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1({[1-(3-isobutylisoxazol-5-yl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-ethylphenyl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 2-[(dipropylamino)carbonyl]-6-methylisonicotinate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-ethynylphenyl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[dipropylamino)carbonyl]-5-(1H-pyrazol-4-yl)benzoate hydrochloride (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1({[1-(3-ethylphenyl)-1-methylethyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-isobutylisoxazol-5-yl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(5-formyl-4-methyl-2-thienyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-isopropylbenzyl)amino]methyl}propyl 5-[(dipropylamino)carbonyl]nicotinate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-isobutylisoxazol-5-yl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-ethynylbenzoate (1R,2R)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(2-isobutyl-1,3-thiazol-5-yl)cyclopropyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(diethylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-pyridin-3-ylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1{[(3-ethylbenzyl)amino]methyl}propyl 5-[(dipropylamino)carbonyl]nicotinate 1-oxide (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(3-formyl-2-furyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-(1-methyl-1H-imidazol-2-y1)benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-pyridin-2-ylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-iodobenzyl)amino]methyl}propyl 2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-[(5-chloro-2-thienyl)sulfonyl]-3-[(1-propylbutyl)sulfonyl]alaninate hydrochloride (1R,2S)-1-({[3-(5-acetyl2-thienyl)benzyl]amino}methyl)-2-amino-3-(3,5-difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(1,3-oxazol-2-yl)benzoate hydrochloride (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(3,5-dimethylisoxazol-4-yl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(4-methyl-2-thienyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1{[(3-ethylbenzyl)amino]methyl}propyl 3-methyl-5-{[methyl(2-pyridin-2-ylethyl)amino]carbonyl}benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1{[(3-iodobenzyl)amino]methyl}proypl 4-hydroxy-3-(pyrrolidin-1-ylcarbonyl)benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 5-oxo-D-prolyl-3-[(1-propylbutyl)sulfonyl]alaninate hydrochloride (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-pyridin-4-ylbenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1{[(3-ethylbenzyl)amino]methyl}propyl 3-(azepan-1-ylcarbonyl)-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3ethylbenzyl)amino]methyl}propyl 5-oxo-L-prolyl-3-[(1-propylbutyl)sulfonyl]alaninate hydrochloride N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-5-{[(2-hydroxyethyl)amino]sulfonyl}-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-ethynyl-N-[(2-isobutyl-1,3-thiazol-5-yl) methyl]-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-isopropylbenzyl)-5-(1,3-oxazol-2-yl)-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-5-(4-methyl-1,3-oxazol-2-yl)-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[(2-isobutyl-1,3-thiazol-5-yl)methyl]-5-(1,3-oxazol-2-yl)-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-ethynyl-N-[(3-isobutylisoxazol-5-yl)methyl]-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-5-(1,3-oxazol-2-yl)-N′,N′-dipropylisophthalamide hydrochloride N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[3-(5-formyl-2-thienyl)benzyl]-5-methyl-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-{[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}-5-methylbenzamide hydrochloride N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-5-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl}-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethynylbenzyl)-5-(1,3-oxazol-2-yl)-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N′,N′-dipropyl-N-[3-(3-thienyl)benzyl]isophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-(1,3-oxazol-2-yl)-N′,N′-dipropyl-N-[3-(trifluoromethyl)benzyl]isophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-5-(piperazin-1-ylsulfonyl)-N′,N′-dipropylisophthalamide dihydrochloride N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-5-(3-methylisoxazol-4-yl)-N′,N′-dipropylisophthalamide hydrochloride N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[1-(3-isobutylisoxazol-5-yl)cyclopropyl]-5-(1,3-oxazol-2-yl)-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[1-(3-ethylphenyl)cyclopropyl]-5-(1,3-oxazol-2-yl)-N′,N′-dipropylisophthalamide N⁴-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N⁴-(3-ethylbenzyl)-6-methyl-N²,N²-dipropylpyridine-2,4-dicarboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-methoxybenzyl)-5-(1,3-oxazol-2-yl)-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[1-(3-ethynylphenyl)cyclopropyl]-5-(1,3-oxazol-2-yl)-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-N′,N′-dipropyl-5-(1H-pyrazol-4-yl)isophthalamide hydrochloride N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[1-(3-ethylphenyl)-1-methylethyl]-5-(1,3-oxazol-2-yl)-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[1-(3-isobutylisoxazol-5-yl)cyclopropyl]-5-methyl-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[3-(5-formyl-4-methyl-2-thienyl)benzyl]-5-methyl-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-isopropylbenzyl)-N′,N′-dipropylpyridine-3,5-dicarboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-ethynyl-N-[1-(3-isobutylisoxazol-5-yl)cyclopropyl]-N′,N′-dipropylisophthalamide N-[(2R,3R)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[1-(2-isobutyl-1,3-thiazol-5-yl)cyclopropyl]-5-methyl-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′,N′-diethyl-N-(3-ethylbenzyl)-5-(1,3-oxazol-2-yl)isophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N′,N′-dipropyl-N-(3-pyridin-3-ylbenzyl)isophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-N′,N′-dipropylpyridine-3,5-dicarboxamide 1-oxide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-ethyl-N-[3-(3-formyl-2-furyl)benzyl]-5-methyl -N′-propylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-5-(1-methyl-1H-imidazol-2-yl)-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N′,N′-dipropyl-N-(3-pyridin-2-ylbenzyl)isophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2hydroxybutyl]-N-(3-iodobenzyl)-2-[(methylsulfonyl)amino]-1,3-oxazole4carboxamide N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N²-[(5-chloro-2-thienyl)sulfonyl]-N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]alaninamide hydrochloride N-[3-(5-acetyl-2-thienyl)benzyl]-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-(1,3-oxazol-2-yl)benzamide hydrochloride N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[3-(3,5-dimethylisoxazol-4-yl)benzyl]-5-methyl-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-[3-(4-methyl-2-thienyl)benzyl]-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-N′,5-dimethyl-N′-(2-pyridin-2-ylethyl)isophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-hydroxy-N-(3-iodobenzyl)-3-(pyrrolidin-1-ylcarbonyl)benzamide 5-oxo-D-prolyl-N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]alaninamide hydrochloride N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N′,N′-dipropyl-N-(3-pyridin-4-ylbenzyl)isophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(azepan-1-ylcarbonyl)-N-(3-ethylbenzyl)-5-methylbenzamide 5-oxo-L-prolyl-N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]alaninamide hydrochloride (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-(2-thienyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1{[(3-ethylbenzyl)amino]methyl}propyl 2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(5-methyl-2-thienyl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-hydroxyisoxazole-5-carboxylate (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-(2-thienyl)propyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(6-methoxypyridin-3-yl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(2,4-dimethoxypyrimidin-5-yl)benzyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3ethylbenzyl)amino]methyl}propyl 3-[(4-hydroxypiperidin-1-yl)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(3-hydroxypiperidin-1-yl)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-methyl-4H,6H-pyrrolo[1,2-a] [4,1]benzoxazepine-4-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl (5-acetyl-2-thienyl)acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-iodobenzyl)amino]methyl}propyl [4-(2-oxopyrrolidin-1-yl)phenyl]acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-{[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}benzoate trihydrochloride (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}-5-methylbenzoate hydrochloride (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 2,8dimethylquinoline-3-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-iodobenzyl)amino]methyl}propyl 7-(1H-imidazol-1-yl)-5,6-dihydronaphthalene-2-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-{[2-(2-hydroxyethyl)piperidin-1-yl]carbonyl}-5-methylbenzoate (1R,2S)-2-amino-1-({[3-(1-benzothien-2-yl)benzyl]amino}methyl)-3-(3,5-difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(benzyloxy)isoxazole-5-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 5-(1H-pyrazol-1-yl)pentanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 1-(2-furylmethyl)-5-oxopyrrolidine-3-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]piperidine-1-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-methoxybenzyl)amino]methyl}propyl 3-[(diethylamino)carbonyl]piperidine-1-carboxylate (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-(2-thienyl)propyl 3-[(dipropylamino)sulfonyl]propanoate (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(2-thienyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate N-[(2R,3S)-3-amino-2-hydroxy-4-(2-thienyl)butyl]-N-(3-methoxybenzyl)-5-methyl-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-[3-(5-methyl-2-thienyl)benzyl]-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-hydroxyisoxazole-5-carboxamide N¹-[(2R,3S)-3-amino-2-hydroxy-4-(2-thienyl)butyl]-N¹-(3-methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[3-(6-methoxypyridin-3-yl)benzyl]-5-methyl-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[3-(2,4-dimethoxypyrimidin-5-yl)benzyl]-5-methyl-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-[(4-hydroxypiperidin-1-yl)carbonyl]-5-methylbenzamide 1-(3-{[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3-ethylbenzyl)amino]carbonyl}-5-methylbenzoyl)-L-prolinamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-[(3-hydroxypiperidin-1-yl)carbonyl]-5-methylbenzamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-4-methyl-4H,6H-pyrrolo[1,2-a] [4,1]benzoxazepine-4-carboxamide 2-(5-acetyl-2-thienyl)-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)acetamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-iodobenzyl)-2-[4-(2-oxopyrrolidin-1-yl)phenyl]acetamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-{[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}benzamide trihydrochloride N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}-5-methylbenzamide hydrochloride N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2,8-dimethylquinoline-3-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-7-(1H-imidazol-1-yl)-N-(3-iodobenzyl)-5,6-dihydronaphthalene-2-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-{[2-(2-hydroxyethyl)piperidin-1-yl]carbonyl}-5-methylbenzamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[3-(1-benzothien-2-yl)benzyl]-5-methyl-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(benzyloxy)-N-(3-ethylbenzyl)isoxazole-5-carboxamide 1-(3-{[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3-ethylbenzyl)amino]carbonyl}-5-methylbenzoyl)-D-prolinamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-5-(1H-pyrazol-1-yl)pentanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-1-(2-furylmethyl)-5-oxopyrrolidine-3-carboxamide N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3-methoxybenzyl)-N³,N³-dipropylpiperidine-1,3-dicarboxamide N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N³,N³-diethyl-N¹-(3-methoxybenzyl)piperidine-1,3-dicarboxamide N-[(2R,3S)-3-amino-2-hydroxy-4-(2-thienyl)butyl]-N-benzyl-5-methyl-N′,N′-dipropylisophthalamide (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[(3S)-2-oxoazepan-3-yl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(1,3-thiazol-2-yl)benzoate dihydro chloride (1R,2S)-2-amino-3-(2furyl)-1-{[(3-methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 5oxo-1-(2-thienylmethyl)pyrrolidine-3-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-[(butylthio)methyl]-5-methyl-2-furoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-(2-oxo-1,3-oxazolidin-3-yl)benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-(1H-pyrrol-1-yl)benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 1,3,4,5-tetrahydrothiopyrano[4,3-b]indole-8-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4,5-dimethyl-2-(1H-pyrrol-1-yl)thiophene-3-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-hydroxy-6-(1-hydroxy-2,2-dimethylpropyl)pyridine-2-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 2,2′-bithiophene-5-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-(1H-imidazol-1-yl)butanoate (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(2-thienyl)propyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate (1R,2S)-2-amino-1-({[2-(aminocarbonyl)-1H-indol-6-yl]amino}methyl)-3-(3,5-difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 2-(1-oxo-1,3-dihydro-2H-isoindol-2-y1)butanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-chloro-4-(methylsulfonyl)thiophene-2-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-[({[(5R)-3-ethyl-2-oxo-1,3-oxazolidin-5-yl]methyl}amino)methyl]propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 5-methyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4,5-dimethoxy-1-benzothiophene-2-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1[({[(5S)-3-ethyl-2-oxo-1,3-oxazolidin-5-yl]methyl}amino)methyl]propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(1,3benzodioxol5-yl)-1-{[(3-methoxybenzyl)amino]methyl}propyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-(3,5-dioxo-1,2,4-triazolidin-4-yl)benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 2-hydroxy-4-oxo-4-(3-thienyl)butanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 2-(1H-1,2,3-benzotriazol-1-yl)hexanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-{[(1-propylbutyl)sulfonyl]methyl}propanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl (5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 5-(benzylthio)nicotinate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 1H-pyrazole-5-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 6-chloro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 1H-benzimidazole-2-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 6-hydroxy-4,7-dimethoxy-1-benzofuran-5-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl [1,2,4]triazolo[4,3-a]pyridine-6-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 2-hydroxy-4-oxo-4-(2-thienyl)butanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 7-hydroxy-4-oxochromane-2-carboxylate N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-[(3S)-2-oxoazepan-3-yl]-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-(1,3-thiazol-2-yl)benzamide dihydrochloride N-[(2R,3S)-3-amino-4-(2-furyl)-2-hydroxybutyl]-N-(3-methoxybenzyl)-5-methyl-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-5-oxo-1-(2-thienylmethyl)pyrrolidine-3-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-[(butylthio)methyl]-N-(3-ethylbenzyl)-5-methyl-2-furamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-4-(2-oxo-1,3-oxazolidin-3-yl)benzamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-4-(1H-pyrrol-1-yl)benzamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-1,3,4,5-tetrahydrothiopyrano[4,3-b]indole-8-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-4,5-dimethyl-2-(1H-pyrrol-1-yl)thiophene-3-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-hydroxy-6-(1-hydroxy-2,2-dimethylpropyl)pyridine-2-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2,2′-bithiophene-5-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-4-(1H-imidazol-1-yl)butanamide N¹-[(2R,3S)-3-amino-2-hydroxy-4-(2-thienyl)butyl]-N¹-benzyl-N³,N³-dipropylbenzene-1,3,5-tricarboxamide N-[2-(aminocarbonyl)-1H-indol-6-yl]-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)butanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-chloro-N-(3-ethylbenzyl)-4-(methylsulfonyl)thiophene-2-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-{[(5R)-3-ethyl-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-methyl-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-5-methyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-4,5-dimethoxy-1-benzothiophene-2-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-{[(5S)-3-ethyl-2-oxo-1,3-oxazolbidin-5-yl]methyl}-5-methyl-N′,N′-dipropylisophthalamide N¹-[(2R,3S)-3-amino-4-(1,3-benzodioxol-5-yl)-2-hydroxybutyl]-N¹-(3-methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-(3,5-dioxo-1,2,4-triazolidin-4-yl)-N-(3-ethylbenzyl)benzamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-hydroxy-4-oxo-4-(3-thienyl)butanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-(1H-1,2,3-benzotriazol-1-yl)-N-(3-ethylbenzyl)hexanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-N-(3-ethylbenzyl)-2-{[(1-propylbutyl)sulfonyl]methyl}propanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-(5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-(benzylthio)-N-(3-ethylbenzyl)nicotinamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-1H-pyrazole-5-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-6-chloro-N-(3-ethylbenzyl)-3-methyl-2-oxo-2,3-dihydro-1,3benzoxazole-5-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-1H-benzimidazole-2-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-6-hydroxy-4,7-dimethoxy-1-benzofuran-5-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl) [1,2,4]triazolo[4,3-a]pyridine-6-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-hydroxy-4-oxo-4-(2-thienyl)butanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-7-hydroxy-4-oxochromane-2-carboxamide (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 2-(2,3-dihydro-1-benzofuran-5-yl)-1,3-thiazole-4-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-{[(1-propylbutyl)sulfonyl]methyl}propanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-oxo-4-[(5-phenyl-1,3,4-thiadiazol-2-yl)amino]butanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[2(2-oxo-2-pyrrolidin-1-ylethoxy)phenyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl (1,1-dioxidotetrahydro-2-thienyl)acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 5-hex-1-yn-1-ylnicotinate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-methoxyisoxazole-5-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 2,3-dimethyl-1H-indole-7-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl (1-methyl-1H-indol-3-yl) (oxo)acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl [5-(4-methylphenyl)-2H-tetrazol-2-yl]acetate (1R,2S)-2-amino-1-{[(3-methylbutyl)amino]methyl}-3-(2-thienyl)propyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 5-methyl-3-phenylisoxazole-4-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-(1H-indol-3-yl)-4-oxobutanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-[(5-benzyl-1,3,4-thiadiazol-2-yl)amino]-4-oxobutanoate ethyl 4-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}oxy)butyl]amino}piperidine-1-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-(2-fluorobenzoyl)-1H-pyrrole-2-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-[4-(2-furoyl)piperazin-1-yl]-4-oxobutanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-oxoisoindoline-1-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl thieno[2,3-b]quinoline-2-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(4-methyl-1,3-oxazol-2-yl)benzoate hydrochloride (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 2-[2-furoyl(methyl)amino]benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 5-hydroxy-1H-indole-2-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 2,2-dimethylchromane-8-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 6-benzylpyrazine-2-carboxylate 4-oxide (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-methyl-4-oxo-3,4-dihydrophthalazine-1-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3,4-dihydro-2H-1,5-benzodioxepine-7-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl [4-(2,5-dioxopyrrolidin-1-yl)phenoxy]acetate (1R,2S)-2-amino-3-(2furyl)-1-{[(3-methoxybenzyl)amino]methyl}propyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (1R,2S)-2-amino-3-(1,3-benzodioxol5-yl)-1-{[(3-methylbutyl)amino]methyl}propyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 6-fluoro-2-hydroxyquinoline-4-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-oxo-4-(2-thienyl)butanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 5-[(4,6-dimethylpyrimidin-2-yl)amino]-5-oxopentanoate N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-(2,3-dihydro-1-benzofuran-5-yl)-N-(3-ethylbenzyl)-1,3-thiazole-4-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-N-(3-ethylbenzyl)-2-{[(1-propylbutyl)sulfonyl]methyl}propanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-N′-(5-phenyl-1,3,4-thiadiazol-2-yl)succinamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-[2-(2-oxo-2-pyrrolidin-1-ylethoxy)phenyl]-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-(1,1-dioxidotetrahydro-2-thienyl)-N-(3-ethylbenzyl)acetamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-5-hex-1-yn-1-ylnicotinamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-methoxyisoxazole-5-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2,3-dimethyl-1H-indole-7-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-(1-methyl-1H-indol-3-yl)-2-oxoacetamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-[5-(4-methylphenyl)-2H-tetrazol-2-yl]acetamide N¹-[(2R,3S)-3-amino-2-hydroxy-4-(2-thienyl)butyl]-N¹-(3-methylbutyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-5-methyl-3-phenylisoxazole-4-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-4-(1H-indol-3-yl)-4-oxobutanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-(5-benzyl-1,3,4-thiadiazol-2-yl)-N-(3-ethylbenzyl)succinamide ethyl 4-([(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]{3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)piperidine-1-carboxylate N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-4-(2-fluorobenzoyl)-1H-pyrrole-2carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-(4-morpholin-4-ylphenyl)acetamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-5-(ethylthio)nicotinamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-4-[4-(2-furoyl)piperazin-1-yl]-4-oxobutanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-oxoisoindoline-1-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)thieno[2,3-b]quinoline-2-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-methyl-4-oxo-3,4-dihydrophthalazine-1-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3,4-dihydro-2H-1,5-benzodioxepine-7-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-[4-(2,5-dioxopyrrolidin-1-yl)phenoxy]-N-(3-ethylbenzyl)acetamide N¹-[(2R,3S)-3-amino-4-(2-furyl)-2-hydroxybutyl]-N¹-(3-methoxybenzyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxamide N¹-[(2R,3S)-3-amino-4-(1,3-benzodioxol-5-yl)-2-hydroxybutyl]-N¹-(3-methylbutyl)-N³,N³-dipropylbenzene-1,3,5-tricarboxamide (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl (4-morpholin-4-ylphenyl)acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 5-(ethylthio)nicotinate N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-6-fluoro-2-hydroxyquinoline-4-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-4-oxo-4-(2-thienyl)butanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-(4,6-dimethylpyrimidin-2-yl)-N-(3-ethylbenzyl)pentanediamide (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(piperidin-3-ylsulfonyl)benzoate dihydrochloride (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 6-chloro-4-hydroxyquinoline-2-carboxylate (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-(2-thienyl)propyl 5-(dipropylamino)-5-oxopentanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl (6-oxo-3-phenylpyridazin-1(6H)-yl)acetate N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-(4-methyl-1,3-oxazol-2-yl)benzamide hydrochloride N-(2-{[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3-ethylbenzyl)amino]carbonyl}phenyl)-N-methyl-2-furamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-5-hydroxy-1H-indole-2-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2,2-dimethylchromane-8-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-6-benzyl-N-(3-ethylbenzyl)pyrazine-2-carboxamide 4-oxide (1R,2S)-2-amino-3-(1,3benzodioxol-5yl)-1-{[(3-methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl (5-pyridin-2-yl-2H-tetrazol-2-yl)acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl isoxazole-5-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-(2,5-dimethyl-1H-pyrrol-1-yl)-3-hydroxybenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-{[5-(cyclopentylmethyl)-1,3,4-thiadiazol-2-yl]amino}-4-oxobutanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl (3-oxo-1,2-benzisothiazol-2(3H)-yl)acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-methyl-5-(pyrrolidin-1-ylcarbonyl)-1H-pyrrol-3-yl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4,6-diethoxypyridine-2-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-(5-methyl-1H-pyrrol-2-yl)-4-oxobutanoate (1R,2S)-2-amino-3-(1,3-benzodioxol-5-yl)-1-[(benzylamino)methyl]propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(piperazin-1-ylsulfonyl)benzoate hydrochloride (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(3-oxo-2,1-benzisothiazol-1(3H)-yl)propanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl (2,6-dihydroxypyrimidin-4-yl)acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 5-oxo-5-[(2-pyridin-2-ylethyl)amino]pentanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl [2-(4-fluorophenyl)-1,3-benzoxazol-5-yl]acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 2-(1,3-dithian-2-yl)-3-furoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 5-methylthiophene-2-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl [(5,7-dimethyl[1,2,4]triazolo[4,3-a]pyrimidin-3-yl)thio]acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-[(1-acetyl-2,3-dihydro-1H-indol-7-yl)amino]-4-oxobutanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 1H-indole-7-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-(1,2,3-thiadiazol-4-yl)benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(4,4-dimethyl-2,5-dioxoimidazolidin-1yl)-2-{[(1-propylbutyl)sulfonyl]methyl}propanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl [1-methyl-3-(methylthio)-1H-indol-2-yl]acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl [(2-{[4-(1,3-oxazol-5-yl)phenyl]amino}-2-oxoethyl)thio]acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-(2-furyl)-4-oxobutanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(3-pyridin-2-yl-1,2,4-oxadiazol-5-yl)propanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl [2-(acetylamino)-1,3-thiazol-4-yl]acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl [(4-methyl-4H-1,2,4-triazol-3-yl)thio](phenyl)acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-(1,3-benzothiazol-2-yl)butanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl [(2-oxo-2,3-dihydroquinazolin-4-yl)thio]acetate N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-(piperidin-3-ylsulfonyl)benzamide dihydrochloride N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-6-chloro-N-(3-ethylbenzyl)-4-hydroxyquinoline-2-carboxamide N-[(2R,3S)-3-amino-2-hydroxy-4-(2-thienyl)butyl]-N-(3-methoxybenzyl)-N′,N′-dipropylpentanediamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-(6-oxo-3-phenylpyridazin-1(6H)-yl)acetamide N-[(2R,3S)-3-amino-4-(1,3-benzodioxol-5-yl)-2-hydroxybutyl]-N-(3-methoxybenzyl)-5-methyl-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)isoxazole-5-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-(2,5-dimethyl-1H-pyrrol-1-yl)-N-(3-ethylbenzyl)-3-hydroxybenzamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N′-[5-(cyclopentylmethyl)-1,3,4-thiadiazol-2-yl]-N-(3-ethylbenzyl)succinamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-(3-oxo-1,2-benzisothiazol-2(3H)-yl)acetamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-5-methyl-N-[1-methyl-5-(pyrrolidin-1-ylcarbonyl)-1H-pyrrol-3-yl]-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4,6-diethoxy-N-(3-ethylbenzyl)pyridine-2-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-4-(5-methyl-1H-pyrrol-2-yl)-4-oxobutanamide N-[(2R,3S)-3-amino-4-(1,3-benzodioxol-5-yl)-2-hydroxybutyl]-N-benzyl-5-methyl-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-(piperazin-1-ylsulfonyl)benzamide hydrochloride N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-(3-oxo-2,1-benzisothiazol-1(3H)-yl)propanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-(2,6-dihydroxypyrimidin-4-yl)-N-(3-ethylbenzyl)acetamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-N′-(2-pyridin-2-ylethyl)pentanediamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-[2-(4-fluorophenyl)-1,3-benzoxazol-5-yl]acetamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-(1,3-dithian-2-yl)-N-(3-ethylbenzyl)-3-furamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-5-methylthiophene-2-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]2-[(5,7-dimethyl[1,2,4]triazolo[4,3-a]pyrimidin-3-yl)thio]-N-(3-ethylbenzyl)acetamide N′-(1-acetyl-2,3-dihydro-1H-indol-7-yl)-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)succinamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-1H-indole-7-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-4-(1,2,3-thiadiazol-4-yl)benzamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-N-(3-ethylbenzyl)-2-{[(1-propylbutyl)sulfonyl]methyl}propanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-[1-methyl-3-(methylthio)-1H-indol-2-yl]acetamide 2-({2-[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3-ethylbenzyl)amino]-2-oxoethyl}thio)-N-[4-(1,3-oxazol-5-yl)phenyl]acetamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-4-(2-furyl)-4-oxobutanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-(3-pyridin-2-yl-1,2,4-oxadiazol-5-yl)propanamide 2-[2-(acetylamino)-1,3thiazol-4-yl]-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)acetamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]-2-phenylacetamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-(1,3-benzothiazol-2-yl)-N-(3-ethylbenzyl)butanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-[(2-oxo-2,3-dihydroquinazolin-4-yl)thio]acetamide (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 1-methyl-1H-indole-2-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl [3-(2-thienyl)-1H-pyrazol-1-yl]acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl (2-thioxo-1,3-benzothiazol-3(2H)-yl)acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 7-fluoro-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-4-oxobutanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 1-benzofuran-3-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 5-oxo-5-(pyridin-3-ylamino)pentanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 2-methyl-4-oxo-4H-chromene-6-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl ({2-[(5-methylisoxazol-3-yl)amino]-2-oxoethyl}thio)acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(1H-imidazol-1-yl)propyl]amino}methyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(1,3benzodioxol5yl)-1-{[(3-methylbutyl)amino]methyl}propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-1-{[(3-methylbutyl)amino]methyl}-3-(2-thienyl)propyl 3-[(dipropylamino)sulfonyl]propanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 6-(2-furoylamino)hexanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl [(1-phenyl-4,5-dihydro-1H-tetrazol-5-yl)thio]acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-(3,4-dihydro-2H-chromen-6-yl)-4-oxobutanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl indolizine-2-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl nicotinate 1-oxide (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 2,3-dihydro-1H-cyclopenta[b]quinoline-9-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-methyl-1H-pyrazole-5-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(1,3-benzothiazol-2-yl)-3-methoxypropanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-{[(methylamino)carbonyl]amino}-3-(3-thienyl)propanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 5-pyridin-2-ylthiophene-2-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl (5,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyridin-3-yl)acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 2-isobutyl-1,3-dioxoisoindoline-5-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 5-(acetylamino)-2-furoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl isoquinoline-4-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl [(4-phenyl-4H-1,2,4-triazol-3-yl)thio]acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl (2-ethyl-4H-[1,2,4]triazolo[1,5-a]benzimidazol-4-yl)acetate (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(2-furyl)propyl 3-[(dipropylamino)carbonyl]-5-methylbenzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 7-chloro-1-benzofuran-2-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(2-oxo-2H-1,3-benzoxazin-3(4H)-yl)propanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl (pyrimidin-2-ylthio)acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-{[3-(aminocarbonyl)-4,5,6,7-tetrahydro-1-benzothien-2-yl]amino}-4-oxobutanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl [(5-phenyl-1,3,4-oxadiazol-2-yl)thio]acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl quinoline-6-carboxylate (1R,2S)-2-amino-1-[(benzylamino)methyl]-3-(2-furyl)propyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-(2,3-dihydro-1,4-benzodioxin6-yl)-4-oxobutanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(1H-indol-3-yl)-1H-pyrazole-5-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 6-chloronicotinate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl (phthalazin-1-ylthio)acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl [(1-oxidopyridin-2-yl)thio]acetate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(acetylamino)-5-fluoro-1H-indole-2-carboxylate (1R,2S)-2-amino-3-(1,3-benzodioxol-5-yl)-1-[(benzylamino)methyl]propyl 3-(aminocarbonyl)-5-[(dipropylamino) carbonyl]benzoate (1R,2S)-2amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-[(5-methyl-1,3,4-thiadiazol-2-yl) amino]-4-oxobutanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl (2-ethyl-1H-benzimidazol-1-yl) acetate (1R,2S)-2amino-3-(1,3benzodioxol-5-yl)-1-{[(3-methoxybenzyl)amino]methyl}propyl 3-[(dipropylamino)sulfonyl]propanoate (1R,2S)-2-amino-3-(3,5difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(2-oxo-1,3-benzoxazol-3(2H)-yl)propanoate (1R,2S)-2-amino-3-(3,5difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-[(6-methylpyridin-2-yl) amino]-4-oxobutanoate 4-((1R,2S)-2-amino-3-(3,5difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl) 3-ethyl (4R)-1,3-oxazolidine-3,4-dicarboxylate N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-1-methyl-1H-indole-2-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophemyl)-2-hydroxybutyl]-5-chloro-N-(3-ethylbenzyl)-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-[3-(2-thienyl)-1H-pyrazol-1-yl]acetamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-(2-thioxo-1,3-benzothiazol-3(2H)-yl)acetamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-7-fluoro-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophehyl)-2-hydroxybutyl]-4-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-N-(3-ethylbenzyl)-4-oxobutanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-1-benzofuran-3-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-N′-pyridin-3-ylpentanediamide (1R,2S)2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 2-methyl-4-oxo-4H-chromene-6-carboxylate 2({2-[[(2R,3S)-3amino-4(3,5difluorophenyl)-2-hydroxybutyl](3-ethylbenzyl)amino]-2-oxoethyl}thio)-N-(5-methylisoxazol-3-yI)acetamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-[3-(1H-imidazol-1-yl)propyl]-5-methyl-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(1,3-benzodioxol-5-yl)-2-hydroxybutyl]-5-methyl-N-(3-methylbutyl)-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-2-hydroxy-4-(2-thienyl)butyl]-3-[(dipropylamino)sulfonyl]-N-(3-methylbutyl)propanamide N-{6-[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3-ethylbenzyl)amino]-6-oxohexyl}-2-furamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-[(1-phenyl-4,5-dihydro-1H-tetrazol-5-yl)thio]acetamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-(3,4-dihydro-2H-chromen-6-yl)-N-(3-ethylbenzyl)-4-oxobutanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)indolizine-2-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)nicotinamide 1-oxide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2,3-dihydro-1H-cyclopenta[b]quinoline-9-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-methyl-1H-pyrazole-5-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(1,3-benzothiazol-2-yl)-N-(3-ethylbenzl)-3-methoxpropanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-{[(methylamino)carbonyl]amino}-3-(3-thienyl)propanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-5-pyridin-2-ylthiophene-2-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-(5 6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyridin-3-yl)-N-(3-ethylbenzyl)acetamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-isobutyl-1,3-dioxoisoindoline-5-carboxamide 5-(acetylamino)-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-furamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)isoquinoline-4-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-[(4-phenyl-4H-1,2,4-triazol-3-yl)thia]acetamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-(2-ethyl-4H-[1,2,4]triazolo [1,5-a]benzimidazol-4-yl)acetamide N-[(2R,3S)-3-amino-4-(2-furyl)-2-hydroxybutyl]-N-benzyl-5-methyl-N′,N′-dipropylisophthalamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-7-chloro-N-(3-ethylbenzyl)-1-benzofuran-2-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-(3-ethylbenzyl) propanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-(2-oxo-2H-1,3-benzoxazin-3(4H)-yl)propanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-(pyrimidin-2-ylthio)acetamide N′-[3-(aminocarbonyl)-4,5,6,7-tetrahydro-1-benzothien-2-yl]-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl) succinamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-[(5-phenyl-1,3,4-oxadiazol-2-yl) thio]acetamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)quinoline-6-carboxamide N¹-[(2R,3S)-3-amino-4-(2-furyl)-2-hydroxybutyl]-N¹-benzyl-N³,N³-dipropylbenzene-1,3, 5-tricarboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-(3-ethylbenzyl)-4-oxobutanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-(1H-indol-3-yl)-1H-pyrazole-5-carboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-6-chloro-N-(3-ethylbenzyl)nicotinamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-(phthalazin-1-ylthio)acetamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-2-[(1-oxidopyridin-2-yl)thio]acetamide 3-(acetylamino)-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-5-fluoro-1H-indole-2-carboxamide N¹-[(2R,3S)-3-amino-4-(1,3-benzodioxol-5-yl)-2-hydroxybutyl]-N¹-benzyl-N³,N³-dipropylbenzene-1,3,5-tricarboxamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbbenzyl)-N′-(5-methyl-1,3,4-thiadiazol-2-yl)succinamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-2-(2-ethyl-1H-benzimidazol-1-yl)-N-(3-ethylbenzyl)acetamide N-[(2R,3S)-3-amino-4-(1,3-benzodioxol-5-yl)-2-hydroxybutyl]-3-[(dipropylamino)sulfonyl]-N-(3-methoxybenzyl)propanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-3-(2-oxo-1,3-benzoxazol-3(2H)-yl)propanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N-(3-ethylbenzyl)-N′-(6-methylpyridin-2-yl)succinamide ethyl(4R)-4-{[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3-ethylbenzyl)amino]carbonyl}-1,3-oxazolidine-3-carboxylate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-{[(3R)-pyrrolidin-3-yloxy]carbonyl}-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-{[(3S)-tetrahydrofuran-3-yloxy]carbonyl}-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-{[2-(acetylamino)ethoxy]carbonyl}-3-(butylsulfonyl)-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-[(pyridin-3-ylmethoxy)carbonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-[(pyridin-4-ylrnethoxy)carbonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-[(pyridin-3-ylmethoxy)carbonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-[(pyridin-4-ylmethoxy)carbonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-({[(3R)-1-acetylpyrrolidin-3-yl]oxy}carbonyl)-3-[(1-propylbutyl)sulfonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-{[(3S)-tetrahydrofuran-3-yloxy]carbonyl}-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-{[(3S)-tetrahydrofuran-3-yloxy]carbonyl}-L-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-[(pyridin-3-ylmethoxy)carbonyl]alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-{[(3S)-tetrahydrofuran-3-yloxy]carbonyl}alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-{[(3R)-tetrahydrofuran-3-yloxy]carbonyl}alaninate (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl 3-[(1-propylbutyl)sulfonyl]-N-{[(3S)-tetrahydrofuran-3-yloxy]carbonyl}alaninate (1R,2S)-2amino-3-(3,5difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-({[(3R)-1-acetylpyrrolidin-3-yl]oxy}carbonyl)-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-{[(3R)-pyrroiidin-3-yloxy]carbonyl}alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-({[(3R)-1-benzylpyrrolidin-3-yl]oxy}carbonyl)-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-({[(3R)-1,1-dioxidotetrahydro-3-thienyl]oxy}carbonyl)-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-{[(3R)-tetrahydro-3-thienyloxy]carbonyl}alaninate (1R,2S)-2-amino-1-[(cyclopropylamino)methyl]-3-(3,5-difibuorophenyl)propyl 3-[(1-propylbutyl)sulfonyl]-N-[(tetrahydro-2H-pyran-4-yloxy)carbonyl]alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-({[1-(methylsulfonyl)piperidin-4-yl]oxy}carbonyl)-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5-diflbuorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-{[(1-acetylpiperidin-4-yl)oxy]carbonyl}-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5-diflbuorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-({[(2R)-5-oxopyrrolidin-2-yl]methoxy}carbonyl)-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-({[(2S)-5-oxopyrrolidin-2-yl]methoxy}carbonyl)-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-isonicotinoyl-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-(pyridin-3-ylcarbonyl)-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-[(2,4-dimethyl-1,3-thiazol-5-yl)carbonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-{[3-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-[(3-methyl-1H-pyrazol-5-yl) carbonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-(1H-imidazol-4-ylcarbonyl)-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-[(6-hydroxypyridin-3-yl)carbonyl]-D-alaninate (1R,2S)-2-amino-1-[(cyclopropylamino)methyl]-3-(3,5-diflbuorophenyl)propyl 3-(butylsulfonyl)-N-(pyridin-3-ylcarbonyl)-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-isonicotinoyl-3-[(1-propylbutyl)sulfonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-[(5-bromopyridin-3-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-[(5-chloropyridin-3-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-[(5-methylpyridin-3-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-{[3-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-[(3-methyl-1H-pyrazol-5-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-(1,3-thiazol-4-ylcarbonyl)-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-[(1-acetylpiperidin-4-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-ethylphenyl)cyclopropyl]amino}methyl)propyl 3-[(1-propylbutyl)sulfonyl]-N-(pyridin-3-ylcarbonyl)-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-ethylphenyl)cyclopropyl]amino}methyl)propyl N-isonicotinoyl-3-[(1-propylbutyl)sulfonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-(pyridin-3-ylcarbonyl)-D-alaninate (1R,2S)-2-amino-3-(3,5difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-(pyridin-3-ylcarbonyl)alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-ethyiphenyl)cyclopropyl]amino}methyl)propyl N-isonicotinoyl-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-[(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 5-oxo-D-prolyl-3-[(1-propylbutyl)sulfonyl]alaninate hydrochloride (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 5-oxo-L-prolyl-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-[3-(4-oxo-2-thioxo-1,3-thiazolidin-3-yl)propanoyl]-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-(piperidin-4-ylcarbonyl)-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-[(2,4-dimethyl-1,3-thiazol-5-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-{[2-methyl-4-(trifluoromethyl)-1,3-thiazol-5-yl]carbonyl}-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-[(3,5-dimethylisoxazol-4-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-[(3-methyl-1H-pyrazol-5-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-(1H-pyrazol-4-ylcarbonyl)alaninate (1R,2S)-2-amino-3-(3,5difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-(1H-imidazol-5-ylcarbonyl)-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-(1H-imidazol-4-ylacetyl)-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5difluorphenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-(pyrazin-2-ylcarbonyl)alaninate (1R,2S)-2-amino-3-(3,5difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-(2,6-dihydroxyisonicotinoyl)-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-[(6-hydroxypyridin-3-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-[(6-chloropyridin-3-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-isonicotinoyl-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-(pyridin-3-ylcarbonyl)alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-(pyridin-2-ylcarbonyl)alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-(1H-indol-6-ylcarbonyl)-3-[(1-propylbutyl)sulfonyl]alaninate hydrochloride (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2S)-2-[(4-methoxy-4-oxobutanoyl)amino]-5-oxo-5-piperidin-1-ylpentanoate (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2R)-2-{[(benzyloxy)carbonyl]amino}-5-oxo-5-piperidin-1-ylpentanoate (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2R)-2-[(3-ethoxy-3-oxopropanoyl)amino]-5-oxo-5-piperidin-1-ylpentanoate (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2R)-2-[(4-methoxy-4-oxobutanoyl)amino]-5-oxo-5-piperidin-1-ylpentanoate (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2R)-2-[(5-methoxy-5-oxopentanoyl)amino]-5-oxo-5-piperidin-1-ylpentanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl N-{[(5-chloro-2-thienyl)thio]peroxy}-3-[(1-propylbutyl)sulfonyl]alaninate (1R,2S)-2-amino-3-(3,5difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-{[(1-propylbutyl)sulfonyl]methyl}propanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(4,4-dimethyl-2,5-dioxoimidazolidin-1yl)-2-{[(1-propylbutyl)sulfonyl]methyl}propanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-{[(1-propylbutyl)sulfonyl]methyl}propanoate (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2S)-2-amino-5-oxo-5-piperidin-1-ylpentanoate (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2S)-2-[(2-methoxy-2-oxoethyl)amino]-5-oxo-5-piperidin-1-ylpentanoate (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2R)-2-amino-5-oxo-5-piperidin-1-ylpentanoate (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2R)-2-[(2-ethoxy-2-oxoethyl)amino]-5-oxo-5-piperidin-1-ylpentanoate (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2R)-2-[(4-ethoxy-4-oxobutyl)amino]-5-oxo-5-piperidin-1-ylpentanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(2-butyl-1,3-dioxolan-2-yl)-N-(methoxycarbonyl)-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(2-butyl-1,3-dioxan-2-yl)-N-(methoxycarbonyl)-D-alaninate (1R,2S)-2-amino-3-(3,5difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl (2R)-4-(2-butyl-1,3-dioxolan-2-yl)-2-[(methoxycarbonyl)amino]butanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl (2R)-4-(2-butyl-1,3-dioxan-2-yl)-2-[(methoxycarbonyl)amino]butanoate (1R,2S)-2amino-3-(3,5-difluorophenyl)-1-{[(3-ethynylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-[(3-methyl-1H-pyrazol-5-yl) carbonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(trifluoromethyl)benzyl]amino}methyl)propyl 3-(butylsulfonyl)-N-[(3-methyl-1H-pyrazol-5-yl)carbonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-ethylphenyl)cyclopropyl]amino}methyl)propyl 3-(butylsulfonyl)-N-[(3-methyl-1H-pyrazol-5-yl) carbonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)1-({[1-(3-ethynylphenyl)cyclopropyl]amino}methyl)propyl 3-(butylsulfonyl)-N-[(3-methyl-1H-pyrazol-5-yl)carbonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-[({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)methyl]propyl 3-(butylsulfonyl)-N-[(3-methyl-1H-pyrazol-5-yl)carbonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 4-butyl-N-[(methylamino)carbonyl]-D-homoserinate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(2-butyl-1,3-dioxolan-2-yl)-N-[(methylamino)carbonyl]-D-alaninate (1R,2S)-2amino3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(2-butyl-1,3-dioxan-2-yl)-N-[(methylamino)carbonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)1-{[(3-ethylbenzyl)amino]methyl}propyl (2R)-4-(2-butyl-1,3-dioxolan-2-yl)-2-{[(methylamino)carbonyl]amino}butanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl (2R)-4- (2-butyl-1,3-dioxan-2-yl)-2-{[(methylamino)carbonyl]amino}butanoate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethynylbenzyl)amino]methyl}propyl 3-(butylsulfonyl)-N-[(4-methyl-1H-pyrazol-1-yl)carbonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[3-(trifluoromethyl)benzyl]amino}methyl)propyl 3-(butylsulfonyl)-N-[(4-methyl-1H-pyrazol-1-yl)carbonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-ethylphenyl)cyclopropyl]amino}methyl)propyl 3-(butylsulfonyl)-N-[(4-methyl-1H-pyrazol-1-yl)carbonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-({[1-(3-ethynylphenyl)cyclopropyl]amino}methyl)propyl 3-(butylsulfonyl)-N-[(4-methyl-1H-pyrazol-1-yl)carbonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-[({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)methyl]propyl 3-(butylsulfonyl)-N-[(4-methyl-1H-pyrazol-1-yl)carbonyl]-D-alaninate (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-[(1-propylbutyl)sulfonyl]-N-[(tetrahydro-2H-pyran-4-yloxy)carbonyl]alaninate β-alanyl-N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(butylsulfonyl)-N¹-(3-ethylbenzyl)-D-alaninamide (1R,2S)-2-amino-1-{[(3-methoxybenzyl)amino]methyl}-3-phenylpropyl (2R)-2-[(4-ethoxy-4-oxobutyl)amino]-5-oxo-5-piperidin-1-ylpentanoate N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(butylsulfonyl)-N¹-(3-ethylbenzyl)-N²-(methoxyacetyl)-D-alaninamide (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1{[(3-ethylbenzyl)amino]methyl}propyl 3-(2-butyl-1,3-dioxan-2-yl)-N-(methoxycarbonyl)-D-alaninate 5-oxo-D-prolyl-N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]alaninamide hydrochloride 5-oxo-L-prolyl-N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]alaninamide N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3-ethylbenzyl)-N²-[3-(4-oxo-2-thioxo-1,3-thiazolidin-3-yl)propanoyl]-3-[(1-propylbutyl)sulfonyl]alaninamide N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N¹-(3-ethylbenzyl)-N²-(1H-imidazol-4-ylacetyl)-3-[(1-propylbutyl)sulfonyl]alaninamide N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-N²-{[(5-chloro-2-thienyl)thio]peroxy}-N¹-(3-ethylbenzyl)-3-[(1-propylbutyl)sulfonyl]alaninamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-N-(3-ethylbenzyl)-2-{[(1-propylbutyl)sulfonyl]methyl}propanamide N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-N-(3-ethylbenzyl)-2-{[(1-propylbutyl)sulfonyl]methyl}propanamide (1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-{[(3-ethylbenzyl)amino]methyl}propyl 3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-{[(1-propylbutyl)sulfonyl]methyl}propanoate (2S)-2-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(3-methoxybenzyl)-5-oxo-5-piperidin-1-ylpentanamide (2R)-2-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(3-methoxybenzyl)-5-oxo-5-piperidin-1-ylpentanamide methyl [(1R)-1-{[[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl](3-ethylbenzyl)amino]carbonyl}-3-(2-butyl-1,3-dioxolan-2-yl)propyl]carbamate methyl [(1R)-1-{[[(2R,3S)-3-amino-4(3,5-difluorophenyl)-2-hydroxybutyl](3-ethylbenzyl)amino]carbonyl}-3-(2-butyl-1,3-dioxan-2-yl)propyl]carbamate N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(2-butyl-1,3-dioxolan-2-yl)-N¹-(3-ethylbenzyl)-N²-[(methylamino)carbonyl]-D-alaninamide N¹-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-3-(2-butyl-1,3-dioxan-2-yl)-N¹-(3-ethylbenzyl)-N²-[(methylamino)carbonyl]-D-alaninamide (2R)-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-(2-butyl-1,3-dioxolan-2-yl)-N-(3-ethylbenzyl)-2-{[(methylamino)carbonyl]amino}butanamide (2R)-N-[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]-4-(2-butyl-1,3-dioxan-2-yl)-N-(3-ethylbenzyl)-2-{[(methylamino)carbonyl]amino}butanamide
 12. A method of generating a compound of formula (Y):

comprising exposing a compound according to claim 1 to aqueous media, wherein R₁, R₂, R₃, R_(N) and R_(C) are as defined in claim
 1. 13. The method of claim 12 wherein the generation of the compound of formula (Y) occurs in vitro.
 14. The method of claim 12 wherein the generation of the compound of formula (Y) occurs in vivo.
 15. The method of claim 12 wherein the aqueous media has a pH of about 2 to about
 10. 16. The method of claim 3 wherein the aqueous media has a pH of about 3 to about
 7. 17. A compound according to claim 1 selected from the group consisting of:


18. A pharmaceutical composition comprising a compound according to claims 1 in combination with a physiologically acceptable carrier or excipient. 